System and Method for Delivery of Regional Citrate Anticoagulation to Extracorporeal Blood Circuits

ABSTRACT

The present invention includes a comprehensive replacement fluid system and method for the delivery of regional citrate anticoagulation (RCA) to extracorporeal blood circuits, wherein the system may include an online clearance monitor (OCM) and a circuit effluent online sensor system (OSS) for the continuous determination of patient plasma content of ultrafilterable solutes.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/528,078 filed Jun. 20, 2012, which is a continuation of U.S.application Ser. No. 12/280,450 filed Dec. 16, 2008, now U.S. Pat. No.8,211,048, issued Jul. 3, 2012, which is the National Stage Entry ofPCT/US2007/062589 filed Feb. 22, 2007, which, in turn, claims thebenefit of U.S. provisional application Ser. No. 60/775,729 filed Feb.22, 2006; U.S. provisional application Ser. No. 60/775,728 filed Feb.22, 2006; U.S. provisional application Ser. No. 60/790,882 filed Apr.11, 2006; U.S. provisional application Ser. No. 60/791,055 filed Apr.11, 2006; and U.S. provisional application Ser. No. 60/845,646 filedSep. 19, 2006, each of which is incorporated by reference herein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a system and method for the delivery ofregional citrate anticoagulation (RCA) to extracorporeal blood circuits.

2. Background Art

Continuous renal replacement therapy (CRRT) is a form of extracorporealblood treatment (EBT) that is performed in the intensive care unit (ICU)for patients with acute renal failure (ARF) or end-stage renal disease(ESRD), who are often hemodynamically unstable with multipleco-morbidities. In a specific form of CRRT, continuous veno-venoushemofiltration (CVVH) (FIG. 1), blood is pumped through a hemofilter anduremic toxin-laden plasma ultrafiltrate is discarded at a rate of 1-10liters per hour (convective removal of solutes). An equal amount ofsterile crystalloid solution (replacement fluid, CRRT fluid) withphysiological electrolyte and base concentrations is simultaneouslyinfused into the blood circuit either before the hemofilter(pre-dilution) or after the hemofilter (post-dilution) to avoid volumedepletion and hemodynamic collapse. From a theoretical and physiologicalpoint of view, when run continuously for 24 hours per day, CVVH is theclosest of all available renal replacement therapy (RRT) modalitiestoday to replicating the function of the native kidneys. Most experts inthe field believe that it should be the preferred treatment modality forunstable patients with renal failure. Nevertheless, 90% of RRT in theICU is performed as intermittent hemodialysis (IHD), sustained lowefficiency dialysis (SLED), or sometimes as continuous veno-venoushemo-diafiltration (CVVHDF). Common to all of these latter methods ofRRT is that the removal of most solutes is predominantly by the processof diffusion from blood plasma through the membrane of the hemofilterinto the dialysis fluid. Diffusion is less efficient in the removal oflarger solutes than convection and therefore, from a theoreticalstandpoint, CVVH is a superior method of RRT.

The most important reason for the limited use of CVVH in the ICU is thatanticoagulation is mandatory to prevent clotting of the extracorporealcircuit in 24-hour treatments. Systemic anticoagulation has anunacceptable rate of major bleeding complications and cannot be donesafely. Similarly, extracorporeal blood treatments includingplasmapheresis, plasma adsorption on specialized columns, blood bankingprocedures, lipid apheresis systems, plasma adsorption-based endotoxinremoval, treatment with a bioartificial kidney device that contains liverenal tubular cells, or with a liver replacement therapy circuit alsorequire powerful regional anticoagulation. Regional citrateanticoagulation has emerged as a possible solution to the clinicalproblem of circuit clotting.

Citrate (or the quickly buffered citric acid) is present in the humanplasma as the trivalent negative citrate anion. This ion chelatesionized calcium in the plasma resulting in a single negative Ca-citratecomplex and in low free ionized calcium levels. Since the coagulationcascade requires free ionized calcium for optimal function, bloodclotting in the extracorporeal blood circuit (EBC) can be completelyprevented by an infusion of citrate into the arterial (incoming) limb ofthe EBC. When the blood is passed through the extracorporeal processingunit, the anticoagulant effect can be fully reversed by the localinfusion of free ionized calcium into the venous (return) limb of theEBC. Therefore, theoretically, regional citrate anticoagulation can beboth very powerful and fully reversible without systemic (intra-patient)bleeding tendencies.

Regional citrate anticoagulation has been performed for more than 20years. Nevertheless, all currently described regional citrateanticoagulation methods are labor intensive and complex with the ICUnurse administering several potentially very dangerous IV infusions inthe circuit and/or in central venous lines with frequent laboratorymeasurements and prescription adjustments. Physician errors inprescription and nursing errors in administration can quickly lead tomajor complications, and even to death. Due to its well-documenteddangers, regional citrate anticoagulation has not gained wide use inclinical practice. The recognized dangers of RCA include hypernatremia;metabolic alkalosis; metabolic acidosis; hypocalcemia 1 (due to netcalcium loss from the patient); hypocalcemia 2 (due to systemic citrateaccumulation); rebound hypercalcemia (due to release of calcium fromcitrate after CVVH is stopped); hypophosphatemia; fluctuating levels ofanticoagulation; nursing and physician errors; ionized hypomagnesemia;declining filter performance; trace metal depletion; accessdisconnection; wrong connection of citrate, calcium infusions, and/or ofthe blood circuit to the patient; and accidental disconnection of thecitrate or calcium infusion.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a prior art system for continuous veno-venoushemofiltration (CVVH) or CVVH with dialysis (CVVHDF);

FIG. 2 illustrates a system according to the present invention for usingcitrate in the pre-dilution solution and infusion of a post-dilutionsolution to enhance removal of citrate in the hemofilter;

FIG. 3 illustrates use of a regional citrate anticoagulation (RCA)system according to the present invention to anticoagulate theextracorporeal circuit of applications other than CRRT;

FIGS. 4 a-4 b illustrate a continuous renal replacement therapy (CRRT)circuit based on pre- and post-dilution hemofiltration with anintegrated online sensor system (OSS) and hematocrit sensors accordingto the present invention;

FIG. 5 a illustrates a hemodialysis system which may be used for 24-hoursustained low efficiency dialysis (SLED) or 4-5 hour intermittenthemodialysis (IHD) with RCA according to the present invention;

FIG. 5 b illustrates a conductivity-based online clearance monitor (OCM)according to the present invention for 24-hour SLED or IHD withonline-generated dialysis fluid and automated RCA;

FIG. 6 a illustrates a hemodialysis system which may be used forcontinuous veno-venous hemodialysis with pre-dilution hemofiltration(CVVHDF or c-SLEDF) with RCA according to the present invention;

FIG. 6 b illustrates a conductivity-based OCM according to the presentinvention for pre-dilution CVVHDF with online-generated therapy fluidand automated RCA;

FIG. 7 a illustrates a hemodialysis system which may be used for4-5-hour post-dilution hemodiafiltration (intermittent post-HDF) withRCA according to the present invention;

FIG. 7 b illustrates a conductivity-based OCM according to the presentinvention for post-dilution hemodiafiltration (HDF) withonline-generated therapy fluid and automated RCA;

FIG. 8 a illustrates a hemodialysis system which may be used forsimultaneous pre- and post-dilution continuous veno-venoushemofiltration (CVVH) or 4-6 hour intermittent high volumehemofiltration (HVHF) with RCA according to the present invention;

FIG. 8 b illustrates a conductivity-based OCM according to the presentinvention for pre- and post-dilution CVVH or HVHF with online-generatedreplacement fluid and automated RCA;

FIGS. 9 a and 9 b illustrate a triple lumen venous catheter with aninfusion pathway according to the present invention;

FIGS. 10 a and 10 b illustrate a quadruple lumen catheter with aninfusion pathway according to the present invention;

FIG. 10 c illustrates a quadruple lumen vascular access catheteraccording to another aspect of the present invention with connectionlines of different lengths and colors;

FIG. 10 d illustrates a quadruple lumen vascular access catheteraccording to another aspect of the present invention with the male andfemale line connectors reversed and of different colors;

FIG. 11 a illustrates connectors according to the present invention usedto attach standard dialysis blood lines (independent arterial and venousblood circuit ends) for dialysis using separate arterial and venousneedles;

FIG. 11 b illustrates connectors according to the present invention usedto attach a citrate-dedicated dialysis blood tubing (different arterialand venous blood circuit ends) for dialysis using separate arterial andvenous needles;

FIG. 12 a illustrates an arterial infusion line connector according tothe present invention which may be used to attach a citrate-dedicateddialysis arterial blood line using separate arterial and venous needles;

FIG. 12 b illustrates a venous infusion line connector according to thepresent invention which may be used to attach a standard orcitrate-dedicated dialysis venous blood line using separate arterial andvenous needles;

FIG. 13 illustrates citrate-dedicated blood circuit tubing withintegrated arterial and venous medication infusion line connectorsaccording to the present invention which may be used to connect theextracorporeal circuit to the patient using separate arterial and venousaccess needles or a double lumen hemodialysis catheter;

FIGS. 14 a-14 b illustrates a triple lumen vascular access catheteraccording to the present invention for use with single needle dialysisoperational mode;

FIGS. 14 c-14 d illustrates a triple lumen vascular access catheteraccording to the present invention for use with single needle dialysisoperational mode that accommodates citrate-dedicated blood tubing andmedication infusion lines with different arterial and venous connectors;

FIG. 15 a illustrates a connector according to the present invention forcircuit priming and for attachment to a single vascular access needlefrom a dialysis blood line set and medication infusion lines for usewith single needle dialysis operational mode;

FIG. 15 b illustrates a connector according to the present invention forcircuit priming and for attachment to a single vascular access needlefrom a dialysis blood line set for use with single needle dialysisoperational mode;

FIGS. 15 c and 15 d illustrate a connector according to the presentinvention for circuit priming and for attachment to a single vascularaccess needle from a citrate-dedicated dialysis blood line for use withsingle needle dialysis operational mode;

FIG. 16 a illustrates a connector according to the present invention forattachment to a single vascular access needle or to a single lumencatheter from a dialysis blood line for use with single needle dialysisoperational mode;

FIG. 16 b illustrates a connector according to the present invention forattachment to a single vascular access needle or to a single lumencatheter from a citrate-dedicated dialysis blood line for use withsingle needle dialysis operational mode;

FIG. 17 a illustrates a hemodialysis system which may be used for24-hour sustained low efficiency dialysis (SLED) or 4-5 hourintermittent hemodialysis (IHD) with RCA according to the presentinvention;

FIG. 17 b illustrates a hemodialysis system which may be used forsimultaneous pre- and post-dilution continuous veno-venoushemofiltration (CVVH) or 4-6 hour intermittent high volumehemofiltration (HVHF) with RCA according to the present invention;

FIG. 17 c illustrates a hemodialysis system with sensors and onlinegeneration of fluid for continuous SLED with RCA according to thepresent invention;

FIG. 17 d illustrates a hemodialysis system with sensors and onlinegeneration of fluid for pre-dilution CVVH with RCA according to thepresent invention;

FIG. 18 depicts a calculation according to the present invention of themaximum possible systemic citrate level during RCA;

FIG. 19 depicts a calculation according to the present invention of theconductivity of plasma (C_(pin)) in the arterial limb of theextracorporeal circuit entering the hemodialyzer;

FIG. 20 a illustrates an OCM in accordance with the present invention;

FIG. 20 b illustrates an OCM in accordance with another aspect of thepresent invention;

FIG. 21 depicts a comparison according to the present invention of theeffects of permanent access recirculation on the fresh dialysis fluidconductivity bolus-based online dialysance measurement (D_(effective))versus the circuit arterial limb blood conductivity bolus-based onlinedialysance measurement (D_(Bolus));

FIG. 22 illustrates a basic hemofiltration circuit according to thepresent invention which may be used to extract a small amount ofultrafiltrate for chemical analysis;

FIG. 23 illustrates a complete hemofiltration circuit according to thepresent invention which may be used to extract a small amount ofultrafiltrate for chemical analysis;

FIG. 24 illustrates a hemofiltration circuit according to the presentinvention which may be used for priming and initial testing of pumps andpressure transducers;

FIG. 25 illustrates a complete hemofiltration circuit according to thepresent invention which may used to extract a small amount ofultrafiltrate for chemical analysis;

FIG. 26 illustrates a hemofiltration circuit according to the presentinvention showing the location of the triple lumen venous catheter withan infusion port at the tip of the withdrawal lumen;

FIG. 27 a illustrates an air gap backflow prevention device which may beused to isolate ultrafiltrate from the patient circuit according to thepresent invention;

FIG. 27 b illustrates a backflow prevention device comprising a seriesof one way valves which may be used to isolate ultrafiltrate from thepatient circuit according to the present invention;

FIG. 27 c illustrates a reduced pressure zone backflow prevention devicewhich may be used to isolate ultrafiltrate from the patient circuitaccording to the present invention;

FIG. 28 a illustrates a hemofiltration circuit according to the presentinvention showing a possible location for a reduced pressure zonebackflow prevention device;

FIG. 28 b illustrates a hemofiltration circuit according to the presentinvention showing a possible location for an air gap backflow preventiondevice;

FIG. 29 a depicts a configuration according to the present invention forderiving the patient systemic solute level (C_(sys)) by measuring theultrafiltrate solute concentration C_(UF) and dividing by the hemofiltersieving coefficient S for the specific solute;

FIG. 29 b depicts a configuration according to the present invention forderiving the patient systemic citrate level C_(sys) by measuring theultrafiltrate citrate concentration C_(UF);

FIG. 29 c depicts a configuration according to the present invention forderiving the patient systemic citrate level C_(sys) by measuring theultrafiltrate citrate concentration C_(UF);

FIG. 30 a is a schematic illustration of a citrate, calcium andmagnesium sensor according to the present invention for use in acontinuously flowing fluid circuit;

FIG. 30 b is a schematic illustration of a citrate sensor according tothe present invention for use in a continuously flowing fluid circuit;

FIG. 31 is a schematic illustration of systemic citrate kinetics duringcitrate anticoagulation including citrate generation, citrate bodyclearance and citrate filter clearance in accordance with the presentinvention;

FIG. 32 is a schematic illustration of solute fluxes in theextracorporeal circuit during CRRT according to the present inventionusing citrate as a small solute example;

FIG. 33 is a graph depicting plasma citrate concentration in the patientduring RCA in accordance with the present invention;

FIG. 34 a is a graph depicting citrate concentration measured by acitrate sensor in the drain circuit of a renal replacement therapymachine utilizing RCA with fixed CRRT prescription settings according tothe present invention that result in the development of a citrate steadystate determined by the CRRT settings and the patient's citratemetabolism;

FIG. 34 b is a graph depicting citrate concentration measured by acitrate sensor in the drain circuit of a dialysis machine utilizing RCAaccording to the present invention; and

FIG. 34 c is a graph depicting the effluent citrate concentration asmeasured by an online filter clearance and patency monitor according tothe present invention.

DETAILED DESCRIPTION OF THE INVENTION

As required, detailed embodiments of the present invention are disclosedherein; however, it is to be understood that the disclosed embodimentsare merely exemplary of the invention that may be embodied in variousand alternative forms. The figures are not necessarily to scale, somefeatures may be exaggerated or minimized to show details of particularcomponents. Therefore, specific structural and functional detailsdisclosed herein are not to be interpreted as limiting, but merely as arepresentative basis for teaching one skilled in the art to variouslyemploy the present invention.

The present invention includes a comprehensive, two replacement fluidsystem and method for the delivery of regional citrate anticoagulation(RCA) to extracorporeal blood circuits, wherein the system may includean online clearance monitor (OCM) and a circuit effluent online sensorsystem (OSS) for the continuous determination of patient plasma contentof ultrafilterable solutes. It is understood that components describedfor one system according to the present invention can be implementedwithin other systems according to the present invention as well.

The system and method according to the present invention is capable ofdelivering RCA to an extracorporeal system requiring anticoagulation.The system addresses the difficulties and risks to patients associatedwith extracorporeal anticoagulation methods and CRRT devices currentlyin use for continuous veno-venous hemofiltration (CVVH). The system mayinclude a combination of various CRRT and dialysis machine hardwarecomponents, a software control module, and a sensor module to measurecitrate or other solute levels online to ensure the maximum accuracy andsafety of treatment prescriptions, and the use of replacement fluidsdesigned to fully exploit the design of the system according to thepresent invention.

With reference first to FIG. 2, a system for CRRT according to thepresent invention is illustrated and designated generally by referencenumeral 10. System 10 includes a CRRT circuit 12 including an arterialblood line 14, a hemofilter 16 in fluid communication with arterialblood line 14, and a venous blood line 18 in fluid communication withhemofilter 16. Arterial and venous blood lines 14, 18 are arranged to beconnected to an access catheter 20 in order to withdraw blood from andreturn blood to a patient. A blood pump 22 is operably connected toarterial blood line 14 in order to facilitate movement of blood fromaccess catheter 20 through CRRT circuit 12. According to one aspect ofthe present invention, blood pump 22 may be precise, with pumping speedswhich may be adjustable in 5 ml/min or finer increments. An effluentline 24 is also in fluid communication with hemofilter 16 for carryingeffluent fluid to a drain to be discarded. An ultrafiltration pump 26may be operably connected to effluent line 24 to facilitate thisprocess, wherein ultrafiltration pump 26 may be an overallultrafiltration pump that may be non-volumetric in a scale-based system,or a net ultrafiltration pump which may be volumetric.

While CRRT circuit 12 is shown and described, it is understood that thesystem according to the present invention may comprise anyextracorporeal circuit, either wholly or only partially outside thebody. Furthermore, it is understood that “patient” as used herein is notlimited to human beings, but may comprise other species as well.

With continuing reference to FIG. 2, system 10 further comprises apre-filter infusion line 28 having a pre-dilution connection 30 toarterial blood line 14 upstream from hemofilter 16. Pre-filter infusionline 28 may supply a pre-dilution solution, such as a citrate-containinganticoagulation solution as described below, from a pre-filter source(e.g., bag 32). A pre-filter replacement fluid pump 34 may be operablyconnected to pre-filter infusion line 28 to facilitate infusion of thepre-dilution solution, wherein pre-filter pump 34 may be implemented asa volumetric pump. A non-volumetric pump may be acceptable withscale-based balancing. Hemofilter 16 may then be used to remove thecitrate anticoagulant (and the bound calcium) from the blood before itis returned to the patient. System 10 may also include a post-filterinfusion line 36 having a post-dilution connection 38 to venous bloodline 18 downstream from hemofilter 16 for restoring the so processedanticoagulated blood to normal volume. Post-filter infusion line 36 maysupply a post-dilution solution, such as an essentially calcium-free,bicarbonate solution as described below, from a post-filter source(e.g., bag 40). A post-filter replacement fluid pump 41 may be operablyconnected to post-filter infusion line 36 to facilitate infusion of thepost-dilution solution, wherein post-filter pump 41 may be implementedas a volumetric pump, although a non-volumetric pump may be acceptablewith scale-based balancing.

In accordance with the present invention, an additional IV infusion line42 and associated IV infusion pump 44 may be utilized for an IV solutioninfusion into venous blood line 18 downstream from post-dilutionconnection 38. In particular, IV infusion pump 44 may be used toadminister a pre-mixed calcium and magnesium-containing infusion from anIV infusion source (e.g., bag 46) in coordination with the CVVHprescription (described below) and patient chemistry values. Patientswill differ in their need for calcium supplementation to reverse thecitrate anticoagulation as they will have different albumin and steadystate citrate levels. There may also be differences in calcium releasefrom or uptake into the bones. Finally, one may have to administer extracalcium and magnesium in the initial few-hour “loading” phase of RCA tosaturate the expanding systemic citrate pool until the steady state isreached. As depicted in FIG. 3, the anticoagulated blood restored tonormal volume with the post-filter replacement fluid infusion can beperfused into any secondary extracorporeal blood treatment (EBT) device48.

FIG. 4 a illustrates additional components which may be included insystem 10 according to the present invention. System 10 may integrateonline (e.g., optical) hematocrit sensors 50 and/or 52 operablyconnected to arterial blood line 14 to determine the dilution of theincoming blood and in communication with an associated display 54.Hematocrit sensors 50, 52 may be deployed in duplicate, one before(sensor 50) and one after (sensor 52) pre-dilution connection 30. Firsthematocrit sensor 50 may be used to determine arterial plasma flow inreal time. Second hematocrit sensor 52 may allow for checking thereliability of the two sensors 50, 52 against each other when thepre-dilution fluid is not running. When the pre-dilution fluid isrunning at a known (machine settings and volumetric pump defined) rate,the readout from hematocrit sensors 50, 52 may allow for thedetermination of the degree of hemodilution with the pre-filterinfusion, and thereby for the calculation of the delivered blood flow tothe dialyzer 16. Online hematocrit sensors 50 and/or 52 allowminute-to-minute calculation of the plasma volume in the blood flowinginto the dialyzer 16. This ensures the most accurate and possiblycontinuously-adjusted dosing of citrate-containing pre-filter fluid toachieve the target citrate to plasma flow ratio. Hematocrit sensors 50and/or 52 can also be used to detect access recirculation. Finally, thereadout from first hematocrit sensor 50 (before the pre-dilutioninfusion) allows for monitoring the patient's blood volume and willdetect excessive net ultrafiltration leading to intravascular volumedepletion with concomitant hemoconcentration in the patient beforehemodynamic compromise could result. Doppler based fluid flow,hematocrit monitors, and volumetric fluid pumps may be used on arterialand venous blood lines 14, 18 as well as the replacement fluid lines 28,36 and effluent fluid line 24 for maximal precision in ensuring that theset blood flow rate on blood pump 22 matches the actual blood flowdelivered by the action of blood pump 22, and that all other fluid flows(pre-filter fluid flow, effluent flow, venous blood flow and netultrafiltration amount) are all the same as defined by the machinesettings.

As shown in FIG. 4 b, a total of four hematocrit sensors 50, 51, 52, 53may be used to determine the dilution of the blood hemoglobin in thearterial limb 14 as well as the venous limb 18 of the extracorporealcircuit 12. FIG. 4 b depicts a comprehensive battery of four onlinehematocrit sensors 50-53 deployed in close physical proximity to eachother, at strategic points of the extracorporeal blood circuit 12 for asingle modular implementation integrated into system 10 according to thepresent invention. Such integration is fully possible and iscontemplated in all other systems described herein. In addition tosensors 50, 52 described above, sensors 51, 53 may be deployed induplicate, one before and one after the post-dilution connection 38. Thevenous limb hemoglobin concentration, which may be determined usingsensor 51, may be temporarily increased by increased ultrafiltration onthe hemofilter 16 with or without a simultaneous decrease in the rate ofinfusion of one or more of the crystalloid fluids used by the system.Conversely, the circuit venous limb hemoglobin concentration (sensor 51)can be temporarily decreased by faster infusion of one or more of thecrystalloid fluids used by the system with or without a simultaneousdecrease in ultrafiltration. The effect on the arterial limb hemoglobinconcentration (sensor 50) of such programmed, intermittent, temporarychanges in the venous limb hemoglobin concentration allow the precise,automated, intermittent calculation of access recirculation, R asapparent to those skilled in the art.

System 10 may further include an integrated online sensor system (OSS)comprising a solute sensor or sensor array 56 operably connected toeffluent fluid line 24 for determining the solute concentration of theultrafiltrate, and in communication with an associated display 58. Inone embodiment, solute sensor 56 may comprise an online citrate sensorwhich may be used to eliminate the risk of undetected citrateaccumulation and may double as an online delivered clearance and liverfunction monitor. Solute sensor 56 may also function as an onlinecalcium and magnesium sensor. The current clinical practice ofmonitoring laboratory parameters every six hours to detect citrateaccumulation is not applicable to the new treatment protocols withhigher clearance goals and a concomitant more rapid citrate accumulationthat would occur with a sudden decline in liver function. More frequentlaboratory testing is clinically not practical. Solute sensor 56according to the present invention allows for the derivation of thecitrate, calcium and magnesium level in the patient's systemic plasma.Under such monitoring, RCA may be performed with complete safety. Thepost-filter fluid summary bicarbonate content could also be adjusted andthe liver function monitored in real time through observing themetabolism of citrate. Solute sensor 56 may also serve as an onlineclearance module.

All of these elements may be coordinated and monitored by a controlprogram, which may be utilized to determine the optimal ratio of pre-and post-dilution fluids and the fluid flow rates required to reachtreatment goals while minimizing citrate load into the patient.

Disposable, sterile fluid circuits may be utilized according to thepresent invention. System 10 may work with, but is not limited to, bloodflows in the range of 50-450 ml/min with flows optimally around the 75to 200 ml/min range (for 24-hour CVVH versus high volume hemofiltration(HVHF) operational mode). This is a benefit, as even the least optimallyperforming catheter access will deliver such flows. According to oneaspect of the present invention, hemofilter 16 may be removable fromsystem 10, so that an appropriate size filter could be used for theprescribed blood flow and hourly ultrafiltration goals, and also so thatelective filter changes could be performed every 24 hours because ofpredictable protein fouling even in the absence of clotting. Morefrequent filter changes may also be needed for the clinical application(e.g. cytokine removal).

Since only convective clearance may be used according to the presentinvention (no diffusive or dialytic component is required), theanticoagulation achieved remains uniform along the axis of hemofilter16, promising superior results when compared with other protocols usingCVVH with simultaneous dialysis (CVVHDF). The amount of middle molecularweight uremic toxin clearance including inflammatory cytokines will alsobe predictably greater than in any prior CRRT implementations. System 10according to the present invention running on a CVVH machine or adedicated device with the necessary pumps and controls may be used tosafely provide citrate anticoagulation to any extracorporeal bloodcircuit, wherein the maximum operational blood flow may be, but is notlimited to, 450 ml/minute.

The RCA system according to the present invention eliminates the risksassociated with a separate concentrated citrate infusion foranticoagulation in CVVH and other extracorporeal circuits. Citrateremoval by hemofilter 16 is important for safe operation of a CVVHsystem using citrate anticoagulation. If hemofiltration is stopped andblood continues to flow through the circuit 12 to prevent coagulation,the separate infusion of citrate has to be stopped immediately or thepatient will receive an excess amount of citrate which could be lifethreatening. In RCA system 10, if for any reason hemofiltration stopsand blood continues to flow through circuit 12 to prevent coagulation(e.g., replacement solution bags 32, 40 are empty), the delivery ofcitrate with the pre-dilution fluid and also the delivery of calciumwith the post-dilution fluid are immediately aborted to protect thepatient from an infusion of excess citrate and calcium.

The RCA system according to the present invention markedly reduces theneed for health care personnel to monitor and adjust CRRT based onhemofiltration. The use of the post-filter fluid provides for enhancedclearance and variability in the treatment prescription with the varyingpotassium and alkali content depending on the fluid selected asdescribed below. Finally, the RCA system according to the presentinvention greatly reduces the risk of citrate accumulation in thepatient associated with RCA during hemofiltration or any otherextracorporeal blood processing intervention. The specific dangers ofRCA as addressed by the RCA system according to the present inventionare explained below:

1) Hypernatremia: Only isonatric solutions may be used including thecalcium solution. Clinically significant hypernatremia (or hyponatremia)due to the treatment cannot occur.2) Metabolic alkalosis: The sum of bicarbonate and anions metabolizableto bicarbonate (in mEq) may be kept between 25-50 mEq bicarbonateequivalents per liter of replacement fluid. This is in keeping withfluid alkali content per liter prescribed in most CVVH protocols in theliterature. Mild metabolic alkalosis with systemic plasma bicarbonate inthe range of 25-30 is possible with high clearance goals but it is notlikely to occur or be clinically highly relevant. Changing the ratio ofthe 25 and 50 bicarbonate bags on the scales (2:0, 1:1, 0:2) and/orsupplementing any post-dilution fluid bag with up to 5 mEq/L NaHCO₃(from standard IV push bicarbonate ampoules) will allow flexibleadjustment of the overall post-dilution fluid bicarbonate content from25 to 55 in about 5 mEq/L increments.3) Metabolic acidosis: With the above flexibility in fluid alkalicontent, it could only develop if citrate were not metabolized. Even so,if the post-dilution fluid is bicarbonate based, life-threatening washout of bicarbonate could not occur with prescriptions with >=50% citrateextraction. Citrate sensor 56 may detect the lack of liver metabolism ofcitrate and may alert the operator to change to a pair of replacementfluids and treatment settings specifically designed for anhepaticpatients. The additional citric acid in the pre-filter fluid is not aneffective acid from the standpoint of the patient, as the bicarbonatesthat it consumes are regenerated through the metabolism of the citrateanion in the liver without any net acid generation (analogous to thecourse diabetic ketoacidosis in a Type 1 diabetic ESRD patient). In thenear anhepatic patient, bicarbonate lost through ultrafiltration willnot be regenerated by citrate metabolism. However, even such patientscan continue on RCA with CVVH, provided that the citrate extractionis >=60%, 50 bicarbonate post-dilution fluid is used, and the calciumhomeostasis is adequately managed with a carefully selected (and higher)dose of the calcium and magnesium infusion.4) Hypocalcemia 1 (due to net calcium loss from the patient): Theultrafiltrate total calcium and magnesium losses are easily calculablein the RCA system according to the present invention. Calcium andmagnesium supplements needed in the form of the dedicated infusionregulated by the system may be calculated by a dosing program alsotaking into account any ongoing citrate accumulation predicted bykinetic modeling and measured by citrate sensor 56. The patient'ssystemic total and ionized calcium levels may be measured every 6 hoursas well as calcium volume of distribution determined by anthropomorphicand citrate sensor data. Magnesium may be dosed to maintain a totalplasma Ca:Mg=2:1 mM ratio (as ionized magnesium measurements are notroutinely available and all chelators of calcium (albumin, citrate, etc)also chelate magnesium.5) Hypocalcemia 2 (due to citrate accumulation): Citrate will be givenin the pre-dilution fluid. This eliminates the risk of nursing errorswith a separate citrate infusion. This protocol achieves equally or moreefficient anti-coagulation than any previous protocol with 30-40% lessnet citrate load into the patient. Careful selection of the pre-filterfluid citrate content and keeping the citrate extraction >=50-66% willeliminate the risk of citrate accumulation beyond 3.75-5 mM. Finally,marked citrate accumulation due to lack of metabolism when it occurs,may also be detected accurately by citrate sensor 56 before the ionizedcalcium could drop by more than 0.25 mmol/L. This may be accomplished byanalyzing the sensor-measured systemic plasma levels of citrate by akinetic modeling program according to the present invention. The kineticprogram analyzes the CVVH prescription (fluid compositions and flowrates as well as blood flow rate) and the sensor data when available. Italso utilizes anthropomorphic data to predict the citrate volume ofdistribution in the patient. Finally the patient's citrate clearance inL/minute may be calculated and subsequently used to generate theexpected citrate accumulation curve and guide calcium and magnesiumreplacement to saturate the retained citrate. In citratenon-metabolizers (patients with liver failure), RCA with CVVH will beeither terminated or carefully continued with special consideration ofthe risk of rebound hypercalcemia at the cessation of RCA and metabolicacidosis from bicarbonate wash-out.6) Rebound hypercalcemia (due to release of calcium from citrate afterCVVH is stopped): The RCA prescription will ensure that systemic citratelevels stay <=3-5 mM corresponding to about maximum 0.6-1 mM chelatedcalcium that could be released after RCA is stopped in all patients whocan metabolize citrate. Most patients will have 1 mM citrate and about0.25 mM Ca chelated by citrate in the steady state. The RCA system andmethod according to the present invention may be designed to keepsystemic ionized Ca levels around 1-1.25 and therefore the highestcalcium level after RCA is stopped will be <=1.6-1.85 mM and mostpatients will rebound to <=1.5 mM Ca levels after treatment. If apatient with liver failure is treated with RCA for CVVH, theprescription may be modified so that the steady state citrate level doesnot exceed 4 mM and the ionized calcium will be maintained at 1.0. A 35ml/kg/hour treatment goal may still be achieved for any patient size.Total magnesium will be kept at 50% of total calcium (mM/mM). This willrequire large doses of the additional calcium and magnesium infusions,as there will be more calcium and magnesium in the ultrafiltrate. If theliver function improves the values will gradually normalize with ongoingCVVH and a reduction in the calcium and magnesium infusion withoutrebound hypercalcemia. If the liver does not improve, reboundhypercalcemia will not occur as the citrate will not be metabolized.Finally, prior to a liver transplant, high volume hemofiltration withoutcitrate anticoagulation can be rendered for a few hours to wash out allcitrate and chelated extra calcium and magnesium before the new liver(with good metabolic function) is put in. This way even the anhepaticpatient will be able to receive high dose RCA for CVVH.7) Hypophosphatemia: Because of the lack of calcium or magnesium, thepre-filter and post-filter solutions both can also be supplemented withphosphate by the manufacturer without the risk of calcium- ormagnesium-phosphate precipitation. The phosphate-containing fluids canbe used even when the serum phosphorus is high as the large filtrationgoals will allow significant net phosphate removal. Conversely, thefluids may also serve to correct hypophosphatemia towards normal whenneeded.8) Fluctuating levels of anticoagulation: The fixed composition of thepre-filter fluid and the blood plasma flow to pre-filter fluid ratiothat is kept fixed during a treatment ensures predictable citrate levelsand very effective anticoagulation in the circuit as well as a clearlydefined hourly citrate load into the patient. Since only convectiveclearance is used, the concentrations of ionized calcium and citrateremain unchanged and uniform along the axis of hemofilter 16, quitedifferent from other protocols using CVVHDF. The consideration of thepatient's hemoglobin, and total plasma protein level allows formaximizing the post-dilution ultrafiltration without inducing excessivehemoconcentration.9) Nursing and physician errors: These are near completely eliminated bythe system and method according to the present invention, as the nurse'srole is mainly to obtain blood samples for total and ionized calcium atspecified intervals and notify nephrology of the results. The nurse mayalso make the needed changes to the mixed calcium and magnesium infusionbased on the dosing program (may be provided as a web application orintegrated into the RCA for CVVH system according to the presentinvention). Since the control program may write the entire prescriptionand continuously monitor the machine settings, physician errors areeliminated. Citrate sensor 56 may obviate the need for any laboratorymonitoring.10) Ionized hypomagnesemia: Since clinical monitoring of ionizedmagnesium is usually not possible, the protocol will aim to maintain a2:1 mM/mM ratio between total plasma calcium and total plasma magnesium.To achieve this, the mM ratio of calcium and magnesium may be fixed at2:1 in the regulated calcium/magnesium infusion. Such dosing ensuresthat total and ionized magnesium levels will be appropriate for thesteady state plasma citrate levels.11) Declining filter performance: Due to the purely convective nature ofsmall solute removal, this is not expected to be a problem beforetransmembrane pressure alarms are generated. Elective filter changesevery 24 hours may be recommended due to the predictable protein foulingof the filters even in the absence of clotting.12) Trace metal depletion: Cationic trace metal supplementation may beprovided with the calcium infusion to restore precise mass balance forthese trace solutes. Should any trace metal be incompatible withchloride as an anion, it can be provided in a higher concentration inthe pre-filter solution.13) Access disconnection: Most patients treated will have catheteraccess with a low risk of accidental disconnection.14) Wrong connection of citrate, calcium, or blood circuit to patient:These errors are prevented by the hardware and disposable tubing setdesign of the system as explained herein.15) Disconnection of the citrate, post-filter or calcium infusion: Thiscan be completely prevented by appropriate circuit tubing design(contiguous connection to the blood line, air in-line detection plusscale based monitoring).

The various solutions and fluids which may be utilized according to thesystem and method of the present invention explained above are nowdescribed. For any description of solutions and fluids herein, exceptwhere expressly indicated, all numerical quantities in this descriptionindicating amounts of material or conditions of reaction and/or use areto be understood as modified by the word “about” in describing thebroadest scope of the present invention. Practice within the numericallimits stated is generally preferred. Furthermore, the phrase“essentially free” is understood to mean that only trace amounts of amaterial, compound, or constituent may be present.

The description of a single material, compound or constituent or a groupor class of materials, compounds or constituents as suitable for a givenpurpose in connection with the present invention implies that mixturesof any two or more single materials, compounds or constituents and/orgroups or classes of materials, compounds or constituents are alsosuitable. Also, unless expressly stated to the contrary, percent, “partsof,” and ratio values are by weight. Description of constituents inchemical terms refers to the constituents at the time of addition to anycombination specified in the description, and does not necessarilypreclude chemical interactions among constituents of the mixture oncemixed.

The replacement solutions that may be used by the system according tothe present invention include solutions which are referred to below as“CitrateEasy” and “BicarbEasy” solutions for CVVH and which may beprovided in two formulations each, described in detail below. Using thesystem and method according to the present invention, the citratesolution may be introduced into extracorporeal circuit 12 before theblood enters hemofilter 16. The system and method of the presentinvention may utilize a combination of pre-dilution and post-dilutionhemofiltration, wherein the pre-dilution solution may be CitrateEasy andthe post-dilution fluid may be BicarbEasy.

CitrateEasy is a near isonatric (to physiologic human plasma) andisoalkalic (to other commercial CRRT fluids and in terms ofmetabolizable bicarbonate equivalent anions per liter) citrateanticoagulant-containing hemofiltration solution. BicarbEasy is abicarbonate-based hemofiltration fluid that may be essentially calciumand magnesium free and contains phosphate. BicarbEasy may bemanufactured in a single chamber bag 40, allowing for ease of use andsignificant cost savings in the process. The post-dilutionultrafiltration provides for maximal fractional extraction of thecitrate load from extracorporeal circuit 12 and for maximal uremicclearance achieved for a given rate of extracorporeal circuit bloodflow. Since CitrateEasy and BicarbEasy are essentially free of calciumand magnesium, phosphate can be added to both for physiologic phosphatebalance. The composition of both the pre-filter and post-filter fluidsand the control algorithm of the system and method according to thepresent invention allows for high blood flows and high per hourclearance rates to be accomplished with the special requirements oftwelve hour daily CVVH and high volume hemofiltration (HVHF), withoutoverloading the patient with citrate or inducing undue acid-base orelectrolyte changes.

The use of the CitrateEasy fluid with the system of the presentinvention eliminates the need for and all the associated risks of aseparate concentrated citrate infusion. Citrate removal by hemofilter 16is important for safe operation of a CVVH system using citrateanticoagulation. The separate infusion of citrate in a traditionalset-up will have to be stopped immediately when solute clearance isaborted or the patient will receive an excess amount of citrate whichcould be life threatening. In the system using CitrateEasy, if for anyreason hemofiltration stops, the delivery of citrate with thepre-dilution fluid is immediately aborted.

Further, while calcium and magnesium are essentially completelyeliminated from the replacement fluids, the net balance of thesedivalent cations in the CVVH circuit may be kept zero in the individualpatient by careful and strictly machine-regulated and coordinated dosingof a combined calcium and magnesium supplement infusion. Nursing errorswith the calcium and magnesium infusion may be eliminated by physicallyintegrating this infusion pump 44 with system 10 for the delivery ofadditional mixed calcium and magnesium into venous blood line 18 ofcircuit 12, ensuring maintenance of physiologic ionized calcium and freemagnesium levels in the patient. The system according to the presentinvention may monitor the rate settings of this pump 44 and may alertthe operator if the value detected is unusual in the light of othertreatment and patient parameters. Finally, the mandatory addition ofphosphate to the pre-filter and post-filter replacement fluid by themanufacturer will eliminate the need for separate intravenous phosphateadministration to prevent hypophosphatemia due to removal by CVVH. Thepre-filter phosphate may yield a further (minor) Ca chelation andanticoagulation as well.

Pre-Filter CitrateEasy fluids:

It is understood that the fluids may be provided in a 1×, 5×, 10×, 50×,or any other concentrated or diluted ratio of the fluid componentsdescribed herein. In addition, citrate could be replaced by isocitrateor another non-toxic, metabolizable calcium chelator. Any suchvariations of the following fluids are fully contemplated.

mmol/L mEq/L Sodium (Na⁺) 135-150   135-150 Potassium (K⁺) 0-4   0-4Citrate (Cit³⁻)  8-16.67 24-50 Acid citrate (CitH₃) 0-10   0-30 Chloride(Cl⁻) 95-120   95-120 Calcium (Ca²⁺) 0-4.0   0-8.0 Magnesium (Mg²⁺)0-2.0   0-4.0 Dextrose 5.5-11.0   5.5-11.0 Phosphate 0.0-5.0   0.0-5.0Inulin    0-few mM     0-few mM PAH    0-few mM     0-few mM Tracemetals Only if incompatible with the Ca infusion

Inulin and PAH may be introduced in their usual, fluoroprobe-, orbiotin-labeled form here to allow online monitoring of glomerularfiltration rate and renal tubular secretory function as described withreference to the online sensor system. In addition, the above solutionmay be provided consisting essentially of all components except forinulin, PAH, and trace metals.

Pre-Filter Solution 1: “CitrateEasy16Ca0K2/4P1”

This is a high citrate fluid with phosphorus added, wherein onepreferred mode of operation is simultaneous pre- and post dilution CVVH.This solution may not be advised for patients with liver failure andinability to attain >=66% citrate extraction and/or preexisting severemetabolic acidosis. This solution works with BicarbEasy25/50Ca0K2/4P1.

mmol/L mEq/L Sodium (Na⁺) 140-145 140-145 Potassium (K⁺) 2 or 4 2 or 4Citrate (Cit³⁻) 14 42 Acid citrate 2 6 Chloride (Cl⁻) 105 or 107 105 or107 Calcium (Ca²⁺) 0 0 Magnesium (Mg²⁺) 0 0 Phosphoric acid (H₃PO₄) 1.251.25 Dextrose 5.5 5.5

The removal of both calcium and magnesium is important to the maximalanticoagulant effect and for the safe addition of phosphate to thefluids. The addition of phosphate is possible as there are no divalentions that could precipitate it. The addition of acid citrate in thisratio is also novel. Finally, the sodium is slightly higher than in mostcommercial replacement fluids.

The CitrateEasy16 fluid is the most likely to yield completely normalplasma electrolyte values with high volume treatments. The lack ofcalcium and magnesium and the acid citrate and basic citrate values incombination with phosphate make this a unique fluid. Adding additionalsolutes to published fluids at the point of use with multiple additiveswould likely be too cumbersome and error prone to be an alternative.

Pre-Filter Solution 1: “CitrateEasy16Ca0K2/4P4”

This is a variation for a pre- and post-dilution system without IVinfusion pump 44. This is a high citrate fluid with more phosphorusadded, wherein one preferred mode of operation is simultaneous pre- andpost dilution CVVH. This solution may not be advised for patients withliver failure and inability to attain >=66% citrate extraction and/orpreexisting severe metabolic acidosis. This solution works withBicarbEasy25/50Ca3.5/K2/4P0.

mmol/L mEq/L Sodium (Na⁺) 145 145 Potassium (K⁺) 2 or 4 2 or 4 Citrate(Cit³⁻) 15.0 45 Acid citrate 1 3 Chloride (Cl⁻) 102 or 104 102 or 104Calcium (Ca²⁺) 0 0 Magnesium (Mg²⁺) 0 0 Phosphoric acid (H₃PO₄) 4 4Dextrose 5.5 5.5

The removal of both calcium and magnesium is important to the maximalanticoagulant effect and for the safe addition of phosphate to thefluids. More phosphate is added, as the post-filter fluid will havecalcium and therefore cannot have phosphate. The acid citrate is reducedbecause of the phosphoric acid.

Pre-Filter Solution 1: “CitrateEasy16Ca2.5K2/4P1”

This is a variation for an isolated pre-dilution system without pump 44.The fluid has calcium added, wherein one preferred mode of operation isisolated pre-dilution CVVH. This solution may not be advised forpatients with impaired liver function. The low 33% citrate extractiondue to the absence of post-filtration may recommend the use of an onlinecitrate sensor for safe treatments.

mmol/L mEq/L Sodium (Na⁺) 145 145 Potassium (K⁺) 2 or 4 2 or 4 Citrate(Cit³⁻) 14 42 Acid citrate 2 6 Chloride (Cl⁻) 112.5 or 114.5 112.5 or114.5 Calcium (Ca²⁺) 2.5 5 Magnesium (Mg²⁺) 1.25 2.5 Phosphoric acid(H₃PO₄) 1.25 1.25 Dextrose 5.5 5.5

The addition of both calcium and magnesium ensures mass balance forthese ions. The anticoagulant effect may be reduced but still good dueto the excess amount of citrate. Similarly, the very low ionized calciumlevels and acidic pH in the fluid bags allows the safe addition ofphosphate by the manufacturer as well.

Pre-Filter Solution 2: “CitrateEasy8Ca0P1”

This less acidic citrate fluid with phosphorus added can be used forpatients with liver failure and an inability to attain >66% citrateextraction (indefinite use) and/or preexisting severe metabolic acidosis(initial use). This solution works with BicarbEasy25/50Ca0K2/4P1.

mmol/L mEq/L Sodium (Na⁺) 145 145 Potassium (K⁺) 2 or 4 2 or 4 Citrate(Cit³⁻) 7 21 Acid citrate 1 3 Chloride (Cl⁻) 124.75 or 126.75 124.75 or126.75 Calcium (Ca²⁺) 0 0 Magnesium (Mg²⁺) 0 0 Phosphate (H₂PO₄ ⁻) 1.251.25 Dextrose 5.5 5.5

The safety of the phosphate-containing CVVH fluid is predicted based oninorganic fluid chemistry principles: sodium and potassium do notprecipitate with phosphate. The addition of phosphate will eliminatehypophosphatemia, a relatively less acute but clinically stillsignificant complication of CVVH seen particularly often when highclearance goals are targeted and achieved. Finally, CitrateEasy shouldcome with at least two different potassium concentrations (2 and 4 mM)to allow flexibility in potassium mass balance handling.

Pre-Filter Solution 2: “CitrateEasy8Ca0K2/4P4”

This is a variation for a pre- and post-dilution system without pump 44.This less acidic citrate fluid with more phosphate added can be used forpatients with liver failure and an inability to attain >66% citrateextraction (indefinite use) and/or preexisting severe metabolic acidosis(initial use). This solution works with BicarbEasy25/50Ca3.5K2/4P0.

mmol/L mEq/L Sodium (Na⁺) 145 145 Potassium (K⁺) 2 or 4 2 or 4 Citrate(Cit³⁻) 7 21 Acid citrate 1 3 Chloride (Cl⁻) 120 or 122 120 or 122Calcium (Ca²⁺) 0 0 Magnesium (Mg²⁺) 0 0 Phosphate (H₂PO₄ ⁻) 4 4 Dextrose5.5 5.5

The safety of the phosphate-containing CVVH fluid is predicted based oninorganic fluid chemistry principles: sodium and potassium do notprecipitate with phosphate. The addition of more phosphate willeliminate hypophosphatemia, even with a calcium-containing, andtherefore phosphate-free, post-filter bicarbonate fluid. The overallacid content of the fluid is nearly unchanged.

Post-Filter BicarbEasy Fluids:

It is understood that the fluids may be provided in a 1×, 5×, 10×, 50×,or any other concentrated or diluted ratio of the fluid componentsdescribed herein.

mmol/L mEq/L Sodium (Na⁺) 135-150 135-150 Potassium (K⁺) 0-4 0-4Bicarbonate 20-60 20-60 Chloride (Cl⁻)  85-120  85-120 Calcium (Ca²⁺)0-4 0-8 Magnesium (Mg²⁺)   0-2.0   0-4.0 Phosphate (PO₄ ³⁻) 0-5  0-15Dextrose  5.5-11.0  5.5-11.0

Post-Filter Solution 3 and 4 (BicarbEasy25Ca0K2/4P1 andBicarbEasy50Ca0K2/4P1):

BicarbEasy25 and BicarbEasy50 are designed to complement theCitrateEasy16 and CitrateEasy8 fluids, and they are provided withvariable potassium content. BicarbEasy50 with CitrateEasy8 may beadvised for patients who have severe preexisting metabolic acidosisand/or liver failure. These patients will have systemic bicarbonatelevels around 15 or less, and for them the use of the CitrateEasy16fluid could possibly lead to dangerous circuit acidification to pH near6.0 or less. The amount of bicarbonate in the BicarbEasy50 solution ismuch more than in the BicarbEasy25 fluid and will provide morebicarbonate through the CVVH circuit when the patient has liver failure,and thus will correct metabolic acidosis faster in other patients whocan metabolize citrate.

The addition of phosphate may be mandatory by the manufacturer and safeas divalent cations (magnesium and calcium) have been essentiallyremoved from the fluids. The phosphate may be provided as a pH-adjustedmix of the tri-basic and di-basic salt in the BicarbEasy solutions toavoid CO₂ gas generation when mixed with bicarbonate in a single bag, orsimply as the tri-basic salt. In the latter case, upon entering theblood, some additional bicarbonate generation (about 2.5 mEq per literof post-filter fluid) will occur as the phosphate picks up hydrogen ionsfrom carbonic acid dissolved in the plasma. Finally, BicarbEasy shouldcome with at least two different potassium concentrations (2 and 4 mM)to allow flexibility in potassium mass balance handling. A majoradvantage is that the BicarbEasy25/50Ca0 fluids can be manufactured in asingle compartment sterile bag 40 as opposed to current bicarbonateformulations that have to separate the bicarbonate in a dedicated secondcompartment because of the risk of Ca-carbonate and Mg-carbonateprecipitation.

Post-Filter Solution 3: “BicarbEasy25Ca0K2/4P1”

May be preferred in combination with CitrateEasy16Ca0K2/4P1 for patientswith no evidence of liver failure or severe preexisting metabolicacidosis.

mmol/L mEq/L Sodium (Na⁺) 140 140 Potassium (K⁺) 2 or 4 2 or 4Bicarbonate 25 25 Chloride (Cl⁻) 113.25 or 115.25 113.25 or 115.25Calcium (Ca²⁺) 0 0 Magnesium (Mg²⁺) 0 0 Phosphate (PO₄ ³⁻) 1.25 about3.75 Dextrose 5.5 5.5

The removal of calcium and magnesium and the addition of tri-basicphosphate provides a novel solution according to the present invention.The phosphate may also be pH-adjusted between the tri-basic and di-basicsalt form to be compatible with the bicarbonate in the fluid without CO₂generation. The exact bicarbonate concentration will depend on theclinical protocol. Higher treatment goals allow (and require) the use oflower bicarbonate concentrations in the post-filter fluid as long ascitrate metabolism is not impaired, to avoid metabolic alkalosis.

Post-Filter Solution 3: “BicarbEasy25Ca3.5K2/4P0”

This is a variation for a pre-post-dilution system without pump 44,which may be preferred in combination with CitrateEasy16Ca0K2/4P4 forpatients with no evidence of liver failure or severe preexistingmetabolic acidosis.

mmol/L mEq/L Sodium (Na⁺) 140 140 Potassium (K⁺) 2 or 4 2 or 4Bicarbonate 29 29 Chloride (Cl⁻) 128.5 or 130.5 128.5 or 130.5 Calcium(Ca²⁺) 3.5 7 Magnesium (Mg²⁺) 1.75 3.5 Phosphate (PO₄ ³⁻) 0 0 Lacticacid with Ca 4 4 Dextrose 5.5 5.5

The addition of a very high calcium and magnesium is a novel solutionaccording to the present invention. The phosphate is removed, and thebicarbonate should be separated from the calcium, magnesium and lacticacid, such as in a traditional two-chamber bag. The exact bicarbonateconcentration will depend on the clinical protocol. Higher treatmentgoals allow (and require) the use of lower bicarbonate concentrations inthe post-filter fluid as long as citrate metabolism is not impaired, toavoid metabolic alkalosis. The lactic acid may be added to ensure anacid pH after the mixing of the contents at the point of use, to lessenthe risk of carbonate precipitation. The bicarbonate content is beforemixing with the lactic acid; after mixing it will be 25.

Post-Filter Solution 4: “BicarbEasy50Ca0K2/4P1”

This solution may be preferred in combination with CitrateEasy8Ca0K2/4P1for patients with liver failure or until severe metabolic acidosis iscorrected.

mmol/L mEq/L Sodium (Na⁺) 140 140 Potassium (K⁺) 2 or 4 2 or 4Bicarbonate 50 50 Chloride (Cl⁻) 88.25 or 90.25 88.25 or 90.25 Calcium(Ca²⁺) 0 0 Magnesium (Mg²⁺) 0 0 Phosphate (PO₄ ³⁻) 1.25 about 3.75Dextrose 5.5 5.5

The removal of calcium and magnesium and the addition of a phosphate isa novel solution according to the present invention. Most importantly,the bicarbonate is very high to compensate for the bicarbonate lost inthe ultrafiltrate through the circuit and for the lack of liverconversion of citrate into bicarbonate in a liver failure patient. Thephosphate may be pH adjusted between the tri-basic and di-basic saltform to be compatible with the bicarbonate in the fluid without CO₂generation and to avoid carbonate formation.

Post-Filter Solution 4: “BicarbEasy50Ca3.5K2/4P0”

This is a variation for a pre- and post-dilution system without pump 44,which may be preferred in combination with CitrateEasy8Ca0K2/4P4 forpatients with evidence of liver failure or severe preexisting metabolicacidosis.

mmol/L mEq/L Sodium (Na⁺) 140 140 Potassium (K⁺) 2 or 4 2 or 4Bicarbonate 54 54 Chloride (Cl⁻) 98.5 or 100.5 98.5 or 100.5 Calcium(Ca²⁺) 3.5 7 Magnesium (Mg²⁺) 1.75 3.5 Phosphate (PO₄ ³⁻) 0 0 Lacticacid with Ca 4 4 Dextrose 5.5 5.5

The addition of a very high calcium and magnesium is a novel solutionaccording to the present invention. The phosphate is removed, and thebicarbonate should be separated from the calcium, magnesium and lacticacid, such as in a traditional two-chamber bag. The high bicarbonateconcentration may be needed in the absence of citrate metabolism. Thelactic acid is added to ensure an acid pH after the mixing of thecontents at the point of use, to lessen the risk of carbonateprecipitation. The bicarbonate content is before mixing with the lacticacid; after mixing it will be 50.

Solution 5:

Concentrated calcium and magnesium chloride infusion (0.5×, 1×, 2×, 4×,20× or other concentrated or diluted formulations) with a 2:1 to 4:1(preferred 2.5:1) Ca:Mg molar ratio.

mmol/L mEq/L Calcium 50 100 Magnesium 25 50 Sodium 150 150 Chloride 300300

Trace metals may be added in a molar ratio to calcium that is the sameas in the ultrafiltrate during CVVH with RCA at a time point when thesystemic blood plasma has normal trace metal and total calcium content.This fluid may be infused into venous blood line 18 of circuit 12 asclose to the venous port of access catheter 20 as possible. A dedicatedIV infusion pump 44 integrated into the system according to the presentinvention may drive the fluid flow. The amount infused may be set by theoperator and monitored for safety by a calcium dosing program to ensurefull coordination with the patient's chemistry values that are updatedregularly, the patient's estimated volume of distribution for calcium,as well as the RCA for CVVH prescription parameters and citrate sensordata. A typical prescription will result in a flow rate of 100-140ml/hour with the above fluid composition. This allows for precisepumping and 10% dosing steps with the PBP pump in use on one commercialdevice (e.g., Prismaflex). It is expected that the rate of the infusionwill be steady and unchanged after the first few hours of treatment withthe system of the present invention and no significant changes to thecalcium infusion rate will be needed.

Finally a circuit priming solution may also be utilized for calibrationof the OSS according to the present invention:

mmol/L mEq/L Sodium (Na⁺) 130-150 130-150 Citrate (Cit³⁻)  1-20  3-60Chloride (Cl⁻) 100-140 100-140 Calcium (Ca²⁺) 0.5-10   1-20 Magnesium(Mg²⁺) 0.25-5   0.5-10 According to one non-limiting aspect of the present invention, apreferred composition may be:

mmol/L mEq/L Sodium (Na⁺) 140 140 Citrate (Cit³⁻) 7 21 Chloride (Cl⁻)124.1 124.1 Calcium (Ca²⁺) 1.7 3.4 Magnesium (Mg²⁺) 0.85 1.7

This solution may be used to prime the circuit at the start of theprocedure and will allow the OSS to test the accurate functioning of thesafety sensors 56 for citrate, calcium and magnesium.

The rationale behind the CitrateEasy and BicarbEasy fluid designsaccording to the present invention is explained below. First, the sodiumcontent may be 140-145 mEq/L, whereas all commercial fluids use a 140sodium solution. It is of note that patients treated with such fluidsoften stay or become hyponatremic to around 136 serum values. Theexplanation may be that the strength of the Gibbs-Donnan effect isslightly different when the same fluid is infused pre-filter orpost-filter (the negatively charged proteins are diluted in thepre-filter infusion mode). The solutions according to the presentinvention may use the industry standard sodium of 140 for thepost-filter fluid and 145 for the pre-filter fluid. The additional 5 mMsodium above usual fluid sodium content may result in serum sodiumlevels around 140-142 in most patients.

The potassium content may be 2.0-4.0 mEq/L. Manipulation of potassiummass balance may be achieved by selecting 2.0 or 4.0 K CitrateEasy andBicarbEasy fluids. Two bags of each fluid may be hung and used at anygiven time. The ratio of 2 and 4 K bags therefore can change from 0:4 to4:0. This will make the overall K content of the summary replacementfluids adjustable in 0.5 mEq increments, satisfactory for all K massbalance purposes. Finally, when only pre-dilution hemofiltration isperformed, the pre-dilution CitrateEasy fluids will have at least a 2.0and 4.0 K formulation with phosphate.

The pre-filter fluid may have an alkali equivalent content of 20 and 40mEq/L. Current hemofiltration fluids usually contain 40-47 mEq/L lactate(1/1 bicarbonate equivalent) or 13.3-14 mmol/L or 40-42 mEq/Ltrisodium-citrate (3/1 bicarbonate equivalent). Even with highclearances achieved with such high alkali equivalent containing fluidsin some protocols, serum bicarbonate stabilizes around 24-28 values andsevere alkalosis does not occur. The exact explanation is unclear, butmay be explained by the unstable patient losing bicarbonate through bodymetabolism as well as ultrafiltration of bicarbonate and themetabolizable anions citrate and lactate, the sum of which could easilyequal 30-40 mEq/L. Whatever the mechanism, it seems prudent to designthe fluid to deliver at least 40 mEq net bicarbonate equivalent citrateper liter in patients who can metabolize citrate. The net alkali contentfor the pre-filter fluids may be fine-tuned with clinical data between35 and 45 mEq/L. These calculations do not apply to the CitrateEasy8fluids which are designed assuming impaired citrate metabolism and relyon the high bicarbonate BicarbEasy50 fluids for alkali mass balance.Variable ratio of similar CitrateEasy 8 and 16 bags (2:0, 1:1 and 0:2)can also be used for citrate dosing flexibility.

The citrate and acid citrate combined content may be mEq/L (24 or 48):The total citrate content will be 8-16 mmol, while the net alkaliequivalent citrate will be only 7-14 mmol or 21-42 mEq, and the acidcitrate content will be 3-8 mEq. Due to the different pKas of the threecarboxyl groups on the citrate molecule, the mixture of the above willyield about equal amounts of citrateNa₃ and citrateNa₂H. Since the ratioof the salt and acid form is near 1/1, the fluid pH will be around thepKa3=6.3. This will have the added benefit of being protective frombacterial growth in the fluid. When the fluid reaches the patient'sblood, the citrateHNa₂ will react with the bicarbonate in the blood togenerate citrateNa₃ and H₂O plus CO₂. Assuming a mixing ratio of 2liters of plasma to 1 liter of pre-filter fluid and ignoring RBCbuffering, the new bicarbonate will be (67% of systemic serum valuesafter dilution)−3. For example, if systemic bicarbonate is 24, thecircuit bicarbonate after the pre-filter fluid infusion will be 13.However, there will also be a 14 mEq/L added alkali equivalent citratein the fluid for a total alkali content of at least 27. The generatedCO₂ will also contribute to the acidification of the circuit and willultimately be eliminated through the circuit and by pulmonary gasexchange. The amount of CO₂ added to the patient's blood is notclinically significant based on calculations as well as the outcomes ofclinical trials of CVVH using concentrated acid citrate dextrose asanticoagulant (ACD-A, Baxter). However, the circuit acidification withthe high local citrate levels will ensure that nearly all calcium in theplasma will be removed from albumin and other proteins and will befreely ultrafilterable. This will make calcium mass balance calculationsin the CVVH circuit very reliable. Bicarbonate levels will be restoredby citrate metabolism in the patient as well as by the alkalinizingeffects of the post-dilution step where citrate will be exchanged forbicarbonate. The circuit acidification may possibly further interferewith blood clotting.

CRRT fluid calcium and magnesium has essentially zero content. Themassive amount of citrate in the pre-filter fluid strips calcium andmagnesium from albumin. Total ultrafilterable calcium will be nearlyequal to total calcium in circuit blood due to this “stripping” ofcalcium from albumin by citrate as well as with significantacidification of the circuit with the pre-filter fluid. The cumulativeultrafilterable calcium content is predicted at 0.25 mM/mM citrate (insystemic blood), 0.2 mM/g stripped from albumin, and 1.25 mM targetedsystemic ionized calcium for a total filterable calcium of 1.5-3.0mmol/liter filtrate after adjusting for the pre-dilution effect,depending on citrate accumulation, albumin level and systemic ionizedcalcium. Individual patients who may markedly differ in their serumalbumin and citrate and therefore total plasma calcium levels cannot bekept in ideal balance without a dedicated Ca and Mg infusion. Therefore,the present invention replaces all of these losses with a dedicatedcalcium and magnesium infusion which may be strictly coordinated withthe operation of the machine. This allows for both pre-filter andpost-filter CRRT fluids with physiological phosphate concentrations, theratio of which can be varied freely, in good agreement with thephysiologic and symmetric fluid concepts according to the pre-postdilution method of the present invention. The lack of calcium andmagnesium allows for single-chamber bicarbonate-based fluid formulation,a major manufacturing advantage over currently existing formulations.

Calcium and magnesium replacement may include trace metals. This iscoordinated strictly with calcium dosing by using a single mixedinfusion of these two cations (and possibly trace metals that are alsochelated by citrate) to account for the filtered losses of calcium,magnesium and trace metals through the CVVH circuit.

Dextrose content may be 5.5 mmol/L. To match the physiologic plasmaglucose concentration, as CVVH is not meant to be a form of nutrition.Recent publications on the improved clinical outcomes with strictglycemic control in the ICU may also warrant the use of hemofiltrationfluid with physiologic glucose content, lower than what was used in thepast. The impact of potentially substantial glucose removal from thediabetic patient with suboptimal blood sugar control and high clearancegoal CVVH will need to be recognized by the ICU team and proper bloodsugar control will need to be maintained.

Phosphate may be about 1.25 mmol/L. The absence of calcium and magnesiumallows the mixing of phosphate in all CRRT fluid bags without the riskof Ca₃(PO₄)₂ or Mg₃(PO₄)₂ precipitation. The addition of phosphate to acommercial single chamber bicarbonate based CRRT fluid is also a realityfor the first time and represents a major improvement over currentlyavailable bicarbonate based solutions. Hypophosphatemia orhyperphosphatemia cannot occur with these fluid designs. Finally,pre-filter phosphate itself may act as an additional anticoagulant byalso chelating calcium to a minor degree.

Citrate content may be 8 or 16 mmol/L and bicarbonate content may be 25or 50 mmol/L. The scales of a Prismaflex machine, for example, can hold2 fluid bags each or a total of 10 liters per scale. Flexibility incitrate dosing (when the plasma flow to pre-filter fluid flow ratio iskept constant at 2:1) may be achieved by varying the ratio of the 8- and16-mmol citrate bags from 0:2 to 1:1 to 2:0. Flexibility in bicarbonatedosing may be achieved by varying the ratio of the 25- and 50-mmolbicarbonate bags from 0:2 to 1:1 to 2:0. Also, the post-filter fluidscan be supplemented with half ampoule (25 mEq) bicarbonate per bag ifneeded for further flexibility.

For reference, pKa values for acids relevant to RCA at 25 C are asfollows:

Citrate1: 3.13 Citrate2: 4.76 Citrate3: 6.40

Carbonic acid1: 6.37Carbonic acid2: 10.33Phosphoric acid1: 2.12Phosphoric acid2: 7.2Phosphoric acid3: 12.67

The present invention includes a control program for determining theoptimal ultrafiltration, pre- and post dilution fluid, and blood flowrates required to reach treatment goals while minimizing citrate loadinto the patient. The control program also estimates supplementalcalcium and magnesium infusion rates and can monitor the settings ofintegrated single calcium plus magnesium infusion pump 44 for addedsafety. The control program can also calculate bicarbonate balance usingeither citrate sensor 56 or clinical laboratory data to inform clinicalcare decisions on replacement fluid selection for the patient. Thiscontrol program may be incorporated into the software of the system usedfor delivering the fluids according to the present invention. Thecontrol program simplifies the use of the system and allows for exactcalculation of the prescribed treatment variables including blood flow,pre-filter fluid flow and post-filter fluid flow, net ultrafiltration,as well as rate of calcium and magnesium supplement infusion.

The physician may select the duration of the treatment, the hourlytreatment goal, and indicate the presence of severe liver dysfunctionand or acidosis. The systemic hemoglobin and albumin concentration mayalso be needed. The control program may then calculate the mosteffective, safe the prescription that can be delivered without dangerouscitrate accumulation in the systemic plasma of the patient. All patients(including those with liver failure) can safely reach the 35 ml/kg/hrtreatment goal for 24-hour CVVH. The clearance goal is expressedcorrected for the degree of pre-dilution. Unique kinetic modelingmodules and citrate sensor 56 may be provided to predict citrateaccumulation, bicarbonate wash-out or accumulation, and the developmentof hypo- or hypercalcemia with any particular prescription before thesecomplications could occur providing a chance for the operator (or theautomated dosing program) to make corrective changes to the treatmentparameters.

Principles of the control algorithm include:1) Operational mode of simultaneous pre- and post-dilution CVVH with twodifferent fluids to maximize single pass citrate extraction onhemofilter 16. The novel addition of a maximal amount of ultrafiltrationpossible for a given blood flow with simultaneous post-dilution(citrate-free) fluid replacement allows enhancing the fractional removalof the citrate load to 50-75% in a single pass through hemofilter 16.This means that the twice as high pre-filter fluid rates can be reachedby use of the system and method according to the present invention withthe same obligatory citrate load into the patient as with prior RCAprotocols. The ultrafiltration may be further doubled by thepost-dilution step. The summary effect is a 3 to 4-fold increase inuremic clearance for the same citrate load. In clinical practice, thiswill allow the treatment of almost all patients to the most aggressivepre-dilution adjusted clearance goal of 35 ml/kg/hr with markedlyenhanced safety.2) Sufficient plasma total calcium to citrate ratio must be achieved foreffective anticoagulation. The total Ca (mM) to citrate (mM) ratio willrange between 2 to 4 in extracorporeal circuit 12. Part of the citratemay be provided as acid citrate in the pre-filter fluid (to furtherenhance anti-coagulation through acidification of thrombin and othercoagulation cascade proteins). The plasma flow may be monitored onlinewith a hematocrit and blood flow sensor module 50, 52. This will allowthe calculation of the delivered calcium load into circuit 12 and willdefine the necessary anticoagulant infusion rate. Both calcium andcitrate do not distribute into the RBC volume.3) The prescription should eliminate the possibility of citrateaccumulation even in the complete absence of liver metabolism (liverfailure). This may be achieved by keeping the citrate single pass plasmaextraction above 66% when the CitrateEasy16 fluids are used in a 2:1plasma to fluid ratio and above 50% when the CitrateEasy8 fluids areused in a 2:1 plasma to fluid ratio. This will limit the systemic plasmacitrate to 3.75-5 mM or less, regardless of liver function.4) The target plasma total calcium level should be defined (usually2-2.5 mmol/L, depending on the serum albumin concentration and theachieved citrate extraction ratio) by the operator. This will have anindirect impact on the systemic plasma ionized Ca content in steadystate. The systemic citrate level will have a modest impact, even in ICUpatients with liver failure, because citrate accumulation beyond 3-5 mMlevels cannot occur when filter performance is maintained at thespecified fluid flow rates.5) Providing prescriptions and therapy fluid compositions that allowexact mass balance calculations for citrate, calcium and magnesium,sodium and bicarbonate (and trace metal minerals).6) Varying the ratio of the different pre-filter fluid bags andpost-filter fluid bags for greater flexibility in citrate andbicarbonate dosing.

In the following description, a glossary of the abbreviations used is asfollows:

Csys: calculated steady state systemic plasma citrate concentration in apatient with zero citrate metabolism (liver failure; worst case scenarioin RCA)E: apparent circuit post-anticoagulant infusion arterial plasma citrateto therapy fluid citrate concentration difference reduction ratio duringa single filter pass (“plasma citrate extraction ratio”)DCit: apparent citrate plasma dialysance when expressed for QP)QB: the total blood flow hereQP: The arterial blood plasma flow (effective blood water flow forcitrate)Cinf: The increase in the arterial plasma citrate concentration as aresult of the pre-filter replacement fluid infusion with thepre-dilution effect removedHgb: hemoglobin concentration in the arterial bloodC8, C16Cit: citrate concentration (mM) in the citrate pre-filter fluidB25, B50: bicarbonate concentration (mM) in the post-filter fluidQuf: net ultrafiltration negative fluid balance goalQCa/Mg: calcium plus magnesium infusion rateQpre: pre-filter citrate based replacement fluid flow rateQpost: post-filter bicarbonate based replacement fluid flow rateDCit: the calculated citrate dialysance (DCit* when expressed for theadjusted QBCit during calculations and DCit when expressed for theunadjusted QP)f: correction factor to obtain the ultrafilterable fraction of Ca fromtotal plasma CaS: sieving coefficient; SCond; SCit)

The control algorithm according to the present invention may include,but is not limited to, the following flow steps:

1) Start machine in pre- and post-CVVH mode.2)

a) Machine advises filter, tubing, citrate pre-filter, bicarbonatepost-filter and calcium solutions.

b) Confirm all disposables are as advised by the machine.

c) Connect tubing to dialyzer (if not pre-connected) and fluid bags.

d) Load tubing onto infusion pumps.

e) Prime system with priming solution.

f) Test system integrity (current machine protocol).

3) RCA priming checks: performed with the circuit arterial and venousends connected in recirculation mode.

a) Confirm accuracy of the OSS by filtering the circuit priming solution(a standard for Ca, Mg and citrate).

b) Alarm: the values returned by the OSS are not accurate, confirmcorrect priming solution, check OSS.

c) Confirm citrate replacement fluid loading onto pre-dilution pump 34by turning on the pump 34 and measuring the increase in citrateconcentration in the drain circuit 24 of the hemofilter 16 (if OSSavailable).

d) Alarm: it is not the citrate infusion solution that is loaded ontothe citrate pump 34 based on effluent citrate changes.

e) Confirm calcium infusion loading onto the calcium pump 44 by turningon the calcium pump 44 and measuring the increase in calcium andmagnesium in the drain circuit 24 of the hemofilter 16 (if OSSavailable).

f) Alarm: it is not the calcium infusion solution that is loaded ontothe Ca²⁺-pump 44 based on effluent calcium changes.

4) Input Patient Information.

a) Sex, height, age, weight (if Watson volume and V_(E) calculations aredesired; minimum data is weight).

b) Minimum laboratory data is hemoglobin, serum albumin, and serumbicarbonate concentration.

5) Treatment Information advised by software based on prior selections.

a) Input: Dialyzer type (determines expected KoACit, SCit).

b) Input: Maximum hemoconcentration allowed in the circuit (may defineas 60%).

c) Input: Daily maximum replacement fluid amount (may be about 80-100liters).

d) Input: Total pre-dilution adjusted plasma clearance goal for CVVH(may be about 40+ liters).

e) Input: Total net ultrafiltration desired per treatment (or over 24hours).

f) Input: Set CRRT machine alarm parameters.

g) Input: Estimated liver plasma citrate clearance: normal 0.5, poor0.25, none 0 (all L/min).

h) Input: Type of calcium solution (ICU versus OPD, likely uniform).

i) Input: Maximum citrate level in systemic blood allowed (may be about4.0 mM).

6) Connect the patient.7) Safety checks after initial patient connection in CVVH mode.

a) Start treatment, confirm citrate is infusing in the arterial limb 14by watching the effluent citrate level (if available).

b) Measure access recirculation with online hemodilution technique (ifavailable).

8) Display Confirmation Alarms.

a) Alarm if more than 10-15% recirculation is detected. The treatmentwill still be safe, but less effective for uremic clearance.

b) Measure Hgb concentration with the online sensor (alarm if more than20% different from initially provided value).

c) Alarm if citrate-containing pre-dilution fluid is not on arteriallimb 14 of circuit 12.

9) Analyze input data.

a) Determine highest post-filtration flow possible as % of QB with sethemoconcentration limit.

b) If plasma fraction of blood is <=0.66, then Program Qpost for theabove maximum post-filtration, minus (QCa/Mg+Quf) for maximum citrateclearance with a given QB and total Qtf. Otherwise, maximumpost-filtration is 50% of QB.

c) The Qpre is always 50% of QP (QP:Qpre=2:1).

d) For citrate single pass fractional extraction, E is(Qpre+Qpost+QCa/Mg+Quf)/(Qpre+QP).

e) The pre-dilution bag C16:C8 ratio is: If E=0.66 2:0, if between0.66-0.6 1:1, if 0.60-0.50 0:2.

f) If E>=0.5 cannot be achieved with CVVH because of limited postUF, useof SLED or CVVHDF may be advised.

g) The post-dilution bag B25:B50 ratio is: Initially 1:1, adjust 2:0(usual), or 0:2 (liver failure).

h) Aim for 10 liters of pre-dilution fluid use every 6 hours so that bagchanges are predictable.

10) Determine prescription and machine settings.

a) Display QB, Qpre and Qpost, Quf, QCa/Mg.

b) Display expected maximum Csys (<=4 mM citrate).

c) Display expected circuit Ca loss (mmol/hour) before replacementinfusion (prescriptions can have uniform QP and DCit versus weightadjusted).

d) Operator selects K content (2K and 4K bags of each fluid type, useratio 2:0, 1;1, 0:2). The 2:0, 1:1, 0:2 ratios of different bags may beused for flexibility in K, citrate and bicarbonate dosing in a systemwhere each scale can hold two 5 L bags at a time.

11) Calcium Dosing.

a) ECit is essentially equal to ECa*f, where f is the correction forultrafilterable fraction (f will be about 0.95 when 2:0, 0.9 when 1:1and 0.8 when 0:2 ratio C16:C8 pre-dilution fluids are used. f may alsohave to be corrected for albumin levels and circuit pH.).

b) Target systemic plasma total Ca (mM) is defined: Use Csys (0.25 mMCa/1 mM citrate), systemic albumin (0.2 mM Ca/1 g/dL) and targetsystemic ionized Ca (target Cai=1.00 mM when systemic citrate is assumedto be equal to Csys=3).

c) Circuit Ca loss in steady state is equal to QP (L/hour)*Targetsystemic total Ca (mM)*ECit*f.

d) QCa/Mg is easily calculated from the circuit Ca loss and Caconcentration of the Ca infusion solution.

e) At the start, the operator may have to give 1-4 amps of Ca-gluconateover 1-2 hours to bring the systemic ionized Ca close to 1.25-1.5.

f) Ca dosing may be completely automated with the OSS integrated intoeffluent line 24.

12) Continuous safety check.

a) Citrate solution is properly on citrate pump 34 and arterial limb 14is arterial (expected constant step-up in effluent citrate frombaseline) (with OSS). Alarm if citrate bag changed to calcium or salineor access connection reversed during operation based on effluent citrateand calcium monitoring with all the above IV fluids having differentingredients.

b) Input: Set access blood flow rate: current (QB) (Alarm: when QB ischanged because of access issues recalculate all pump speeds and fluidflows).

c) Input: Measured hemoglobin concentration (Alarm: when changed by morethan 10% alert operator to possible bleeding or over-ultrafiltration;recalculate prescription, recommend CBC check, net ultrafiltrationtarget revision).

13) 6 Hourly safety check: input data.

a) Input: measured venous blood gas (VBG) and ionized Ca on the arteriallimb before citrate or on the venous limb 18 of the blood circuit 12after the Ca infusion (Systemic arterial blood gas (ABG) or VBG withionized Ca also acceptable).

b) Systemic total and ionized Ca if indicated only.

c) Hemoglobin every 12 hours (or online with sensor).

d) Albumin once daily or if receiving albumin/plasma products.

e) Hourly net UF goal if changed.

f) Test OSS with zero QB and with filtering the standard primingsolution.

14) Recalculation of the prescription.

a) Re-calculate: maximum post-filtration, maximum ECit, bicarbonate fluxthen adjust.

b) Pre-filter fluid C16:C8 ratio.

c) Post-filter fluid B25:B50 ratio.

d) Supplement either B25 or B50 with ½ amp NaHCO3 per 5 L bag if needed.

e) Adjust rate of QCa/Mg infusion.

f) Adjust QB (to adjust QP) and Qpre to use about 10 L/6 hourspre-filter fluid (keep QP:Qpre 2:1).

15) Other alarms.

a) Change filter electively every 24-48 hours to prevent protein foulingeven in the absence of clotting.

b) Change entire circuit every 72 hours.

c) Replace OSS sensors as needed regularly.

System 10 according to the present invention may contain an OSS formeasuring calcium, magnesium and citrate in the ultrafiltrate. Asexplained herein, the calcium, magnesium and citrate values measuredfrom the ultrafiltrate by the OSS can be used to back-calculate thevalues in the patient's plasma. As also explained, the kinetic curve ofsystemic plasma citrate concentration can be used to derive the exactvalue of the liver clearance of citrate as well as the volume ofdistribution of citrate, V_(E). Using the above parameters, systemiccitrate levels can be accurately predicted at any future T time point.The calcium pump 44 and citrate pump 34 as well as the entireprescription including the therapy fluid bicarbonate concentration (whenflexible) can then be completely controlled by the machine softwareaccording to the present invention.

Filter performance can be monitored by online citrate clearancemeasurements. The direct citrate clearance measurements again enablecomplete precision in calcium and citrate dosing. Since calcium exitsthrough hemofilter 16 almost entirely as Ca-citrate complex, themeasured citrate dialysance will be nearly equal to the total calciumdialysance. The slightly lower Ca-dialysance will be due to theGibbs-Donnan effect and the minimal albumin-bound Ca in circuit 12(about 5-20% depending on the amount of citrate infused in the arteriallimb 14 of the circuit 12, the acidity of the citrate infusion and theplasma albumin level).

In further accordance with the present invention, an RCA system isprovided which may include an online clearance monitor (OCM) and cansafely provide fully automated RCA with any online fluidgeneration-based modality of RRT currently in clinical use. Thisembodiment of the RCA system is designated generally by referencenumeral 110 and is illustrated in FIGS. 5-8, wherein components similarto those described for system 10 are given like reference numeralsexcept for the addition of a “1” prefix. System 110 is capable ofsimultaneous pre- and post-dilution hemofiltration for the greatesttherapy fluid efficiency. The online fluid generation system of RCAsystem 110 may follow the traditional two—(acid and base) concentratecomponent design, thus allowing the greatest variability in the finalsodium and bicarbonate concentration to best suit the needs ofindividual patients. Finally, system 110 also incorporates a dialysismachine module to measure conductivity of the fresh online therapy fluidas well as the filter effluent fluid. These measurements are obtained inconjunction with alterations of the citrate anticoagulant solutioninfusion rate and are analyzed using calculations markedly differentfrom prior art. The method according to the present invention allowsprecise online clearance measurements even in CRRT operational modeswhich is not possible with the prior art, and thus allows the continuousmonitoring of the filter performance (clearance). This, in turn, ensuresthe maintenance of the efficacy and safety of the treatmentprescription.

RCA system 110 can safely provide therapy to critically ill patientseven if they have acute liver failure with inability to metabolizecitrate. The system design prevents citrate accumulation in the patient,while maintaining highly efficient anticoagulation of the extracorporealcircuit. System 110 can also provide fully regionally anticoagulatedblood to any extracorporeal blood circuit, such as up to a maximumoperational blood flow of 500 ml/minute. System 110 is thus suitable toaccommodate the emerging hybrid therapies that combine uremic soluteclearance with plasmapheresis or plasma adsorption by running theanticoagulated blood through specialized adsorption columns or plasmaseparation devices. Following citrate removal in the dialyzer, theanticoagulated blood could also be perfused through a bioartificialkidney device that contains live renal tubular cells or through a MARSliver replacement therapy circuit before the reversal of anticoagulationby the calcium infusion. RCA system 110 achieves these goals withminimal input from the operator and delivers the treatment without anyneed for intervention in all modes of operation. This will broaden thesettings in which a 12 to 24-hour CRRT procedure can be performed andwill likely increase its utilization. System 110 can also be used toprovide highly effective and safe RCA for any modality of RRT includingin-center intermittent hemodialysis or hemodiafiltration and homequotidian or nocturnal hemodialysis, making it applicable to the fargreater market of outpatient RRT sessions where heparin anticoagulationis not preferred.

As will be described in greater detail below, system 110 according tothe present invention also utilizes novel therapy fluid concentrates, anovel citrate anticoagulant and novel single premixed calcium plusmagnesium infusions that have been designed to fully exploit thesystem's capabilities. A control algorithm is provided which derives asafe treatment prescription according to the treatment goals selected bythe operator. Special access catheters and/or special circuit tubingconnectors allow system 110 to provide RCA as soon as the blood entersthe catheter tip (or the circuit tubing from the access needle). Thesingle needle operational mode eliminates the concerns about accessdisconnection.

The following describes a comprehensive system and method according tothe present invention for providing highly effective and completely safeRCA for a hemodialysis machine 160 designed for CRRT. With reference toFIGS. 5 a, 6 a, 7 a, and 8 a, system 110 includes a CRRT circuit 112which includes arterial blood line 114, hemofilter 116, and venous bloodline 118. System 110 includes a blood pump 122 which should ensure asaccurate as possible agreement between the set and delivered blood flow.System 110 may also include volumetric balancing chambers 162 forcoordinating total ultrafiltration and CRRT replacement fluid infusionvolumes, obviating the need for the machine operator to rely on ascale-based system with frequent measurement and exchange of variousfluid bags.

Volumetric balancing chambers 162 include a replacement fluid pump(e.g., volumetric) that diverts a portion of the online therapy fluidfor pre- or post-dilution hemodiafiltration (FIG. 6 a). Fluid removed bythis pump subtracts from the total fresh therapy fluid delivered to thehemofilter 116. The action of the balancing chamber 162 ensures that allfresh therapy fluid delivered to the extracorporeal circuit as apre-dilution replacement infusion, post-dilution replacement infusion,or dialysis fluid is precisely equal to the total circuit effluent minusa small portion of the effluent that is diverted before such balancingby the net ultrafiltration pump. This volumetric pump may infuse about75% of the therapy fluid either as pre-dilution replacement fluid(simultaneous pre-post-dilution CVVH) or as dialysate in pre- orpost-dilution hemodiafiltration. Finally, this pump may pump 100% of thetherapy fluid as dialysis fluid in pure hemodialysis. Additional pump(s)164 (e.g. volumetric) may be provided to divert a portion of the onlinetherapy fluid for pre-dilution hemodiafiltration (FIG. 6 a),post-dilution hemodiafiltration (FIG. 7 a), or simultaneous pre- andpost-dilution hemodiafiltration (FIG. 8 a). Another volumetric pump maydivert a small portion of the effluent fluid as net ultrafiltrate beforethe bulk of the effluent enters the volumetric balancing chamber. Stillanother optional pump is an additional blood pump that is only needed ifthe single-needle dialysis mode is used. The benefit of this operationalmode is that the machine immediately detects accidental accessdisconnection. This is of great clinical value when a permanent access(fistula or graft) is used for CRRT in the ICU or for nocturnalhemodialysis in-center or at home.

System 110 according to the present invention may include a volumetric,precise IV infusion pump 134 for the infusion of concentrated citrateanticoagulant into the arterial limb 114 of the extracorporeal circuit112. Pump 134 may operate in the 0.1-20 ml/min flow rate range and maybe precise to ±3% of the prescribed rate. Also, for essentiallycontinuous flow of the pumped liquid, the volume per single pumpingcycle may be in the 0.05-0.2 ml/cycle range. In one implementation, thispump 134 may have a dedicated air detector controlling a line clamp (notshown). A volumetric, precise IV infusion pump 144 may be provided forthe infusion of concentrated calcium and magnesium chloride into thevenous limb 188 of the extracorporeal circuit 112 to restore calcium andmagnesium mass balance. The same pump specifications would apply here asfor the citrate pump 134. In one implementation, this pump 144 may alsohave a dedicated air detector controlling a line clamp (not shown). Allof the above-described pumps may be operated and monitored for safety bya control algorithm built into the hemodialysis machine softwareprogram.

FIG. 5 a depicts a system with pumps and fluid connections suitable forsustained low efficiency dialysis (SLED) or 4-5 hour intermittenthemodialysis (IHD). FIG. 6 a depicts a system with pumps and fluidconnections suitable for continuous veno-venous hemodialysis withpre-dilution ultrafiltration (CVVHDF). FIG. 7 a depicts a system withpumps and fluid connections suitable for post-dilution hemodiafiltration(HDF). FIG. 8 a depicts a system with pumps and fluid connectionssuitable for continuous simultaneous pre- and post-dilution veno-venoushemofiltration (CVVH) or 4-6 hour intermittent high volumehemofiltration (HVHF).

RCA system 110 may include a conductivity-based online clearance monitor(OCM) 170 that provides precise measurement of the delivered smallsolute clearance in any operational mode. FIGS. 5 b, 6 b, 7 b, and 8 billustrate a conductivity-based OCM according to the present inventionwith online-generated dialysis fluid and automated RCA corresponding tothe different treatment scenarios depicted in FIGS. 5 a, 6 a, 7 a, and 8a, respectively, wherein all of the parameters are known or measuredexcept C_(p) and C_(pin). OCM 170 according to the present invention mayinclude conductivity sensors 172, 174 operably connected to line 176carrying filtered sterile pyrogen-free online therapy fluid and line 178carrying effluent fluid, respectively. Precise dosing of RRT based onconductivity dialysance will provide pharmacists with invaluable datafor medication dosing and will aid clinical research in CRRT.

Automated self-check methods for proper circuit fluid connectionsaccording to the present invention may be provided to provide safetymonitoring of the RRT circuit connections. At startup, before thepatient is connected to the extracorporeal circuit 112, the machine 160may automatically fill the blood circuit with priming solution and mayremove air from all infusion lines as well. The machine 160 may then runa few-minute mock treatment session with the priming solution instead ofblood recirculating in the blood circuit. During this time, loading ofthe calcium pump 144 and the citrate pump 134 with the appropriateinfusion solution may be confirmed by giving a bolus from each pump andconfirming the expected change in the filter effluent conductivityappropriate for the pumped medication infusion. This startup method willutilize the fact that the conductivity of the citrate anticoagulant andthe calcium infusion is markedly different. During this startup period,the baseline filter conductivity dialysance may also be obtained withpriming solution in the circuit and compared with the value expected forthe filter and the prescription fluid flow rates. Significantdifferences may trigger a filter alarm. After the proper loading of themedication pumps is confirmed with the effluent conductivity method, thepatient may be connected and the blood circuit tubing filled with blood.

The machine 160 may then give a small priming solution bolus in theblood circuit and check for access recirculation by looking for anyhemodilution in the arterial limb 114 of the blood circuit using theonline hematocrit sensor 150. If recirculation is detected, the machine160 may prompt the operator to review the access connections and/or theaccess itself. After assessing for recirculation, the machine 160 maydeliver a citrate bolus into the arterial limb of the blood circuitconnected to the citrate pump 134 and may compare the imaged change infilter effluent fluid conductivity with what is expected. If the citratepump 134 is infusing into the venous limb 118 due to wrong connection,the bolus will not be seen in the filter effluent and the machine 160will halt the citrate infusion and alert the operator to the wrongconnection. During this initial citrate bolus, the baseline filterconductivity dialysance may also be obtained, now with blood in thecircuit, and compared with the expected value for the filter and theprescription fluid flow rates. Significant differences may trigger afilter alarm. Finally, if during a treatment interruption the patient isremoved from the machine, and the blood circuit is subsequently wronglyreconnected leading to venous infusion of the citrate anticoagulant, theresultant marked change (drop) in the filter effluent conductivity maybe immediately detected and may cause a machine alarm and cessation ofthe citrate infusion and RRT delivery until the connections are reviewedby the operator.

The RCA system 110 eliminates the risks associated with the nursesdosing a concentrated citrate and or calcium infusion foranticoagulation during a CRRT or other extracorporeal blood treatmentprocedure that uses RCA. Citrate removal by the hemofilter 116 isimportant for safe operation of a CRRT system using citrateanticoagulation. If solute removal is stopped and blood continues toflow through the extracorporeal circuit to prevent coagulation, theinfusion of the anticoagulant solution has to be stopped immediately orthe patient will receive an excess amount of citrate which could be lifethreatening. In RCA system 110, if for any reason solute removal stopsand blood continues to flow through the extracorporeal circuit toprevent coagulation (for example: when the machine has adialysate/replacement fluid conductivity alarm), the delivery of citrateas well as any calcium plus magnesium replacement infusion isimmediately aborted to protect the patient from receiving an excessiveamount of citrate and or calcium plus magnesium.

The automated RCA system 110 according to the present invention markedlyreduces the need for health care personnel to monitor and adjust theCRRT. Significant modifications to the software running the hemodialysismachine 160 are necessary to provide online conductivity dialysancemeasurements during CRRT and support the various operational modes withRCA according to the present invention. The control program (describedbelow) allows tailoring of the prescription to the specific treatmentobjectives and the individual patient's condition with scientificaccuracy by defining only a few variables. Calcium infusion dosing ispredictive and automated. Finally, the RCA system 110 eliminates therisk of citrate accumulation in the patient associated with RCA duringhemofiltration or any other extracorporeal blood processingintervention, such as up to blood flow rates of 500 ml/min. This isexpected to finally bring this treatment modality from highlyspecialized academic health care institutions to a broad group ofpatients and to allow the safe operation of the procedure by lessexperienced health care personnel in most (not-academic) health caresettings.

The RCA system 110 eliminates the dangers of prior RCA protocols in CRRTas discussed below:

1) Hypernatremia: The coordinated and carefully calculated pre-filterinfusion of the anticoagulant citrate and use of the online generatedtherapy fluid solution always ensures the adherence to anoperator-selected final sodium concentration in the summary fluids thatcome into contact with the patients' blood in the range of 135 to 145 aswell as attaining a selected (usually 140 mM) sodium concentration inthe venous blood returning to the patient.2) Metabolic alkalosis: The sum of bicarbonate and anions metabolizableto bicarbonate (in mEq) may be kept between 25-40 mEq bicarbonateequivalents per liter of summary therapy fluid. This is in keeping withfluid alkali content per liter prescribed in most high dose CRRTprotocols in the literature. Since the therapy fluid bicarbonateconcentration can be freely adjusted in the range of 25-40 mM, thiscomplication will be eliminated or easily corrected.3) Metabolic acidosis: The system does not depend on citrate metabolismto provide bicarbonate to the patient. The prescriptions will keep thesystemic citrate level in a narrow range (0-3 mM) regardless of liverfunction. Therefore metabolic acidosis will not develop even in thepatient with severe liver failure and no significant citrate metabolismand even anhepatic patients can continue on high dose CRRT with RCAsystem 110 without the need for separate bicarbonate supplementation.4) Hypocalcemia 1 (due to net calcium loss from the patient): Theultrafiltrate total calcium and magnesium losses are preciselycalculable in system 110 that measures conductivity dialysance directlyand calculates Ca and Mg dialysance indirectly. The combined calciumplus magnesium infusion regulated by the machine 160 will be dosed bythe control program also taking into account any initial citrateaccumulation predicted by kinetic modeling. It is expected that thesystem 110 will be fully automated and that no changes to the infusionrate will be needed during therapy. Such predictive dosing will alsoenable the operator writing the CRRT prescription to specify or “dialin” the target systemic plasma total calcium level that corresponds to atarget (normal) ionized calcium level in the given patient. Clinicalprudence will likely mandate that the patient's systemic total andionized calcium levels continue to be measured every 6 hours withadjustments made to the infusion as required (but such adjustments arenot expected). Magnesium will be dosed to maintain a total plasmaCa:Mg=2:1 to 2:0.8 molar ratio (as ionized magnesium measurements arenot routinely available and all calcium chelators (albumin, citrate etcalso chelate magnesium).5) Hypocalcemia 2 (due to citrate accumulation): Citrate will be givenby a machine controlled IV pump 134. This eliminates the risk of nursingerrors with a separate citrate infusion. The default mode of RCA system110 provides for 75% or higher citrate extraction on the hemofilter 116in a single pass during CRRT. This eliminates the possibility of markedsystemic citrate accumulation even in the absence of liver metabolism.Appropriate calcium infusion dosing will prevent the initial mildhypocalcemia due to a limited systemic citrate buildup. This will beaccomplished by using the estimated systemic plasma levels of citrate aspredicted by a kinetic modeling program. The kinetic program analyzesthe CRRT prescription (fluid compositions and flow rates as well asblood flow rate). It also utilizes anthropomorphic data to predict thecitrate volume of distribution in the patient. Finally, for safety thepatient's citrate clearance in L/minute will be estimated as zero, togenerate the expected citrate accumulation curve and guide calcium andmagnesium replacement to saturate the retained citrate in the first fewhours of the treatment. In all patients, RCA system 110 will always berun in the safest mode with no possibility of citrate accumulation orsignificant metabolic acidosis.6) Rebound hypercalcemia (due to release of calcium from citrate afterCRRT with RCA is stopped): System 110 may not allow treatmentprescriptions that could result in systemic citrate levels in excess ofabout 3 mmol/L. This will ensure that systemic citrate levels stay <=3mM corresponding to about maximum 0.6 mM chelated calcium that could bereleased after RCA is stopped in all patients who can metabolizecitrate. (Most patients will have 1 mM plasma citrate and about 0.25 mMCa chelated by citrate in the steady state). The RCA protocol accordingto the present invention is designed to keep systemic ionized Ca levelsaround 1-1.25 and therefore the highest calcium level after RCA isstopped will be <=1.5-1.75 mM and most patients will rebound to 1.5 mMCa levels after treatment.7) Hypophosphatemia: In all operational modes except short outpatientdialysis or HVHF, the online generated pre-filter therapy fluid can besupplemented with physiologic amounts of phosphate by the manufacturerof the concentrate without the risk of calcium- or magnesium-phosphateprecipitation. The phosphate-containing fluid can be used even when theserum phosphorus is high, as the large clearance goals will allowsignificant net phosphate removal while the hyperphosphatemia ispresent. Conversely, the pre-filter fluid will also serve to correcthypophosphatemia towards normal when needed.8) Fluctuating levels of anticoagulation: The high citrate to calciumratio maintained in the circuit 112 (and the marked pre-dilution in someoperational modes) ensures predictable citrate levels and very effectiveanticoagulation in the circuit 112 as well as a clearly defined hourlycitrate load into the patient.9) Nursing errors: The RCA system 110 is designed so that the nurses orother operators only need to ensure timely supply of the fluids used bythe system 110 and regular laboratory monitoring for total and ionizedcalcium as clinical prudence dictates. Therefore, nursing errors arenear completely eliminated by the system design, as the nurse's role ismainly to obtain blood samples at specified intervals and notify theoperating physician of the results as well as possibly manuallyenter/confirm treatment prescriptions as specified.10) Rare: Ionized hypomagnesemia: Since clinical monitoring of ionizedmagnesium is usually not possible, the method according to the presentinvention may aim to maintain a 2:1 molar ratio between total plasmacalcium and total plasma magnesium. To achieve this, the molar ratio ofcalcium and magnesium may be fixed at 2:1 in the RCA system-regulatedcalcium plus magnesium infusion as well as in some 1× therapy fluids(dialysate). Such dosing ensures that total and ionized magnesium levelswill be appropriate for the steady state plasma citrate levels.11) Declining filter performance: The novel conductivity-based onlineclearance monitor will detect this complication and alert the operatorthat the filter needs to be replaced. The optical hematocrit sensors 150can detect access recirculation and can enable the correction of bloodbolus-based clearance measurements as well as derived systemic citrateand calcium levels for this phenomenon.12) Trace metal depletion: Cationic trace metal supplementation may beprovided with the calcium infusion to restore precise mass balance forthese trace solutes. Any trace metal incompatible with the calciuminfusion can be provided in the citrate anticoagulant infusion in anadjusted concentration.13) Access disconnection: Needle disconnection can be safely detected ifa single needle operational mode is used in combination with the novelcircuit tubing connector to access a permanent access for CRRT or dailynocturnal dialysis.14) Wrong connection of citrate, calcium or acid concentrate or bloodcircuit to patient: These errors are prevented by the hardware design ofthe system 110 as well as through conductivity monitoring based safetychecks.15) Disconnection of the calcium and or citrate infusion: This can becompletely prevented by appropriate circuit tubing design(non-disconnectable, physically continuous infusion to blood lineconnection). The disconnection of the citrate infusion can also bedetected by monitoring the circuit effluent conductivity and or citrateconcentration.

For use with RCA system 110, an anticoagulant citrate solution may beprovided according to the present invention with 5.33:0.66 molar ratioof tri-sodium citrate and acid citrate and a total concentration in the100 to 500 mmol/L range. At a plasma flow of 100 ml/min, a 150 mMsolution will be infused around 240 ml/hour. The acid citrate contentwas reduced to increase the conductivity and allow safe (from thestandpoint of circuit acidification) intermittent bolusing for onlineclearance measurements. The citrate concentration will be the highestallowed by the FDA that still allows precision in delivering exactamounts of sodium citrate boluses during the clearance measurements. Ifthe solution according to the present invention is not available, acommercially available tri-sodium citrate can be used (139 mmol/L) atabout 260 ml/min at 100 ml/min plasma flow. In one modificationspecifically contemplated herein, trace metal minerals that areincompatible with the calcium infusion may be added to the above citratesolutions in a concentration sufficient to restore circuit mass balancefor the specific trace metal mineral. Finally, the concentration of thecitrate solution may also be correlated with the calcium infusion tomake sure these two fluids have markedly different conductivities.

In addition, the anticoagulant citrate solution may contain sodiumchloride in the 0-4000 mmol/L concentration range to increase theconductivity of the solution. The fluid may contain NaCl at about 150mM. This will increase the accuracy of the novel conductivity-basedclearance monitor without requiring the use of highly concentratedsodium citrate solutions. The higher sodium and chloride content of theanticoagulant is easily compensated for by reducing the sodium andchloride content of the online dialysis and/or replacement fluid ifneeded. The addition of any concentrated electrolyte solution (includingthe other specific example of sodium bicarbonate in the 0-2000 mmol/Lconcentration range when only basic citrate anticoagulant is used) tothe citrate anticoagulant solution to increase its conductivity for thepurposes of online clearance monitoring through conductivitymeasurements and to identify the solution through its measuredconductivity is fully contemplated in accordance with the presentinvention.

Novel acid concentrates may be designed according to the concentrateproportioning systems of the hemodialysis machine 160. The final 1×therapy fluid concentrations are defined for all operational modes (the34× acid and base concentrate compositions follow from the 1× values asapparent to those skilled in the art). The acid concentrates in oneimplementation will have essentially zero Ca, Mg and citrate content andsome will have (in the case of the CRRT concentrates) phosphate in them.The unique acid concentrates may be diluted and mixed with the standardbicarbonate concentrate. However, in a variation of all the unique CRRTacid concentrates, the phosphate will not be added to the acidconcentrate but rather it will be in the base concentrate as anapproximately 20:1 mixture of di- and mono-sodium phosphate salt to bepH compatible with the bicarbonate. The purely diffusive and convectiveoperational modes in CRRT may perform well with a single fluid design.This acid concentrate design is presented for procedural simplicity andflexibility for all CRRT. The same single acid concentrate withoutphosphate is suitable for all intense, 4-5 hour outpatient HVHF, HDF orIHD operational modes.

A novel calcium plus magnesium chloride mixed infusion with a Ca:Mgmolar ratio of 2:1 (range 4:1 to 2:1) and in one implementation a totalCa about 200 mmol/L and total Mg about 80 mmol/L is contemplated withthe possible simultaneous use of a traditional, lower conductivitycitrate anticoagulant. At a plasma flow of 100 ml/min, this will resultin a 40-70 ml/hour calcium infusion rate. The dilution of the solutionwill be selected to ensure the precision of dosing (a reasonablyconcentrated solution will be used as allowed by the pumping precisionof the IV pump). In another application, the solution will be moredilute with a total Ca about 50 mmol/L and total Mg 25 mmol/L with thepossible simultaneous use of a high conductivity novel citrateanticoagulant. In one modification contemplated herein, trace metalminerals may be added to the above solutions with each specific tracemetal having a specific predefined molar ratio to calcium (similar tothe concept for magnesium). This molar ratio (for each specific tracemetal species) will be the same as the molar ratio of total calcium tothe total specific trace in the RRT circuit effluent during RCA. (Thisratio, in turn, may be about the same as their respective total molarconcentration ratio in human plasma during RCA.) The ratio for eachtrace metal will be refined based on results of clinical mass balancestudies.

Finally, in one embodiment, all calcium replacement solutions may besupplemented with sodium chloride to a final concentration of 150 mmol/Lfor easier sodium mass balance calculations and also to modulate thefinal conductivity of the fluid. The addition of any concentratedelectrolyte solution (including the specific example of sodium chloridein the 0-2000 mmol/L concentration range) to the calcium replacementsolution for the purposes of easier mass balance calculations and toincrease its conductivity to help identify the solution through itsmeasured (directly, or indirectly through its effects on the filtereffluent) conductivity is fully contemplated in accordance with thepresent invention.

The novel fluids which may be used by RCA system 110 according to thepresent invention are detailed below. Common to all 1× final dialysatecompositions is the fact that they are generated by diluting and mixingan acid and a base concentrate. The shown separation of the componentsinto the acid and base concentrates was chosen to best accommodate theonline fluid generation system of the dialysis machine (Fresenius 2008)used for initial testing. However, all permutations of separations ofthe components of the final dialysates in all concentrated and dilutedformulation including, but not limited to, a 0.25×-50× concentrationrange that by mixing would result in the same 1× online fluid are fullycontemplated. Also, all concentrates can be provided as dry powders aswell to be dissolved and diluted with water. For online therapy fluids,the complete 1× fluid, as well as the portion of the individual solutecomponents coming from the acid concentrate are defined herein.

Citrate Anticoagulant Solutions for RCA System 110:

For all patients receiving CRRT (pre-post-dilution CVVH, pre-dilution24-hour CVVHDF, or 24-hour SLEDD), the usually used anticoagulantsolution is a 5.33:0.66 molar mixture of basic and acid citrate:

1. Acid Citrate Anticoagulant 1 for CRRT:

Acid Citrate Anticoagulant 1 for CRRT: about 4% w/v total citrate; amixture of basic and acid citrate in a 8:1 molar ratio mmol/L mEq/LSodium chloride 150 150 Total Citrate 150 450 Trisodium (Basic) Citrate133.33 400 Citric Acid 16.67 50

The hypertonic sodium content makes online clearance measurementspossible and more accurate with the novel method described earlier. Theaccuracy is greatest when the fluid sodium concentration is highest,limited by taking into account the precision of the sodium citrate pump134. The conductivity increment of the anticoagulant over normal plasmais also significantly (150%) different from the calcium infusion todetect an accidental mix-up of the infusates. The acid component isincluded for its antibacterial effects during storage and also as itcontributes to predictable circuit calcium-albumin dissociation as wellas anticoagulation by a separate circuit acidification effect. Thissolution is around the 4% weight per volume concentration (w/v) limitfor citrate recommended by the FDA for direct infusion.

2. Acid Citrate Anticoagulant 2 for Short, Intense IHD, HDF or Pre-PostHVHF:

Acid Citrate Anticoagulant 2 for short, intense IHD, HDF or pre-postHVHF: about 4% w/v total citrate; a mixture of basic and acid citrate ina 2:1 molar ratio mmol/L mEq/L Sodium Chloride 250 250 Total Citrate 150450 Trisodium (Basic) Citrate 100 300 Citric Acid 50 150

These acid citrate anticoagulants are different from the prior art(e.g., the ACD-A Solution of Baxter) as they contain no dextrose andhave a higher total citrate and sodium content. The acidity of theanticoagulant is very important and provides for further disruption ofthe coagulation cascade beyond the chelation of calcium. In solution 2,the proportion of the acid is increased as the total amount of citratemixed with a liter of plasma is reduced in shorter, more intensive renalreplacement therapy sessions. (The need for intense anticoagulation isless here as filter clotting only needs to be averted for 4-5 hours asopposed to days in CRRT). The sodium concentration is highest to allowprecise online clearance measurements, and more importantly, to allowthe use of a low sodium content in the special acid concentrates usedfor RCA, making it possible for the system to detect these concentratesthrough the lower conductivity of the final therapy fluid generated atstandard dilution ratios with their use. This is important to avoid theaccidental use of a low or zero calcium acid concentrate meant for RCAduring an RRT session without RCA and the combination of moderatelylower sodium acid concentrates and final dialysis fluids with highersodium anticoagulant infusions is specifically contemplated according tothe present invention.

The two anticoagulant fluids described above have identical total molarcitrate content to eliminate the chance of a severe citrate dosing errorif one solution is inadvertently used instead of the other and also haveidentical sodium (and conductivity) content to allow uniformity duringthe online clearance measurements. FDA recommendations on maximumcitrate content of infusates may mandate the use of fluids with totalcitrate content limited to 4% w/v. However, this may not be necessary asthese fluids are part of the extracorporeal circuit and are immediatelydiluted there. The strictly machine-controlled administration of theseinfusates ensures that no concentrated citrate can enter the patient'sbody. Anticoagulant solutions with basic to acid citrate ratio 2:1 to8:1, and total millimolar citrate content 50 to 1000 mmol/L arecontemplated according to the present invention, along with totalcitrate content around 4% w/v. Anticoagulant solutions with only basiccitrate (50-1200 mmol/liter citrate) and additional sodium bicarbonateor sodium chloride either or both in the range of 0-2000 mmol/L toincrease the conductivity are also contemplated. Finally, anticoagulantinfusions with similar designs but the citrate molecules replaced byother chelators of calcium that are safe for human infusion in largeamounts (for example isocitrate) are also fully contemplated inaccordance with the present invention.

Novel Calcium Plus Magnesium Premixed Single Replacement Solution:

A concentrated calcium and magnesium chloride infusion having a 0.25×-4×continuous range diluted/concentrated formulations with a 2:1 (range 1:1to 4:1) molar ratio of calcium and magnesium are provided according tothe present invention. All other possible formulations with similar Caand Mg content and with any anion accompanying these cations that can beused for human IV infusion are also fully contemplated including, butnot limited to, lactate, acetate or gluconate.

1. CaCl2 and MgCl2 Infusion in the Venous Blood Circuit Limb Near theAccess Catheter or Needle:

A. CaCl2 and MgCl2 infusion in venous limb near catheter mmol/L mEq/LCalcium 50 100 Magnesium 25 50 Sodium 150 150 Chloride 300 300 Tracemetals see text see text

B. CaCl2 and MgCl2 infusion in venous limb near catheter mmol/L mEq/LCalcium 200 400 Magnesium 80 160 Sodium 150 150 Chloride 710 710 Tracemetals see text see text

The above are the most likely formulations of the infusion and are basedon the novel concept that under any operating conditions during RCA forCRRT, calcium and magnesium is lost from the extracorporeal circuit inthe effluent fluid in a roughly 2:1 to 2:0.8 molar ratio (depending onthe steady sate citrate level in the patient's plasma), corresponding tothe molar ratio of these ions in human plasma under normal physiologicconditions (about 2.4:1) as altered by the accumulated modest systemiccitrate levels. Therefore, the calcium plus magnesium infusion thatrestores the normal total calcium and magnesium content of blood in thevenous limb of the circuit should also contain these ions in a 2:1 to2:0:8 molar ratio. Such a solution may be important to the optimalperformance of RCA with CRRT. With a plasma flow of about 100 ml/min andcorresponding calcium and magnesium losses in the circuit, the abovemore dilute (A) fluid will provide convenient flow rates of 200-300ml/hour. More dilute (A; such as for CRRT) and concentrated (B; such asfor outpatient HD) forms of the above solution with calcium to magnesiummolar ratio in the range of 1:1 to 4:1 are also contemplated.

Selection of the proper calcium content will be guided by the need forprecise pumping (more dilute fluid preferred) and the need for limitedvolume to be infused and conductivity to be different from that of thecitrate anticoagulant solutions. The idea to use online conductivitymeasurement of either the citrate and calcium infusion fluids directly(such as with a non-contact, sterile method) or the changes in filtereffluent fluid conductivity in response to a presumed (if the infusionbags are connected appropriately) citrate anticoagulant and/or calciuminfusion bolus to detect accidental mix-up of the citrate and calciuminfusions is novel according to the present invention.

Trace Cationic Metal Element Supplementation with the Calcium Infusion:

In their cationic form, trace elements like chromium, copper, manganese,molybdenum, selenium, zinc and iron are chelated by citrate. It isexpected that citrate will strip many or all of these trace metals fromtheir carrier proteins in the plasma and will remove them from thepatient's body through the extracorporeal circuit. Similar to theconcept of proportional magnesium removal detailed above, it is expectedthat the removal of the trace metals will be proportional to the removalof calcium, according to their individual renal replacement therapycircuit effluent molar concentration ratios to the effluent calcium.Therefore, the present invention provides a calcium plus magnesiuminfusion that is supplemented by the cationic trace metals present inhuman plasma, in a fixed molar ratio to the calcium in the infusion asdefined by their total calcium to total trace metal molar concentrationratios in the circuit effluent during RCA, plus or minus 100% range inthe molar concentration ratio. The anion accompanying the Ca²⁺, Mg²⁺ andcationic trace metals will have to be compatible with all cationswithout precipitation and will have to be safe for IV infusion. Thelikely candidates include, but are not limited to, chloride, lactate,gluconate or acetate. All possible formulations with any suitable anionof this calcium plus magnesium and multiple trace element infusion thatsatisfies the above molar ratio requirements are fully contemplated inaccordance with the present invention. In a separate approach, it isalso possible to provide the trace element replacement with the citrateanticoagulant, the dialysis fluid or with the pre- or post-dilutionreplacement fluid infusion, therefore the present invention alsocontemplates supplementing these fluids with trace metal elements torestore mass balance for these metals during regional citrateanticoagulation.

Finally, all calcium replacement solutions may be supplemented withsodium chloride to a final concentration of 150 mmol/L for easier sodiummass balance calculations and also to modulate the final conductivity ofthe fluid. The addition of any concentrated electrolyte solution(including the specific example of sodium chloride in the 0-4000 mmol/Lconcentration range) to the calcium replacement solution for thepurposes of easier mass balance calculations and to increase itsconductivity to help identify the solution through its measured(directly, or indirectly through its effects on the filter effluent)conductivity is fully contemplated according to the present invention.

Bicarbonate with Phosphate for any Treatment Modality:

In one embodiment of the novel 1× dialysate formulations, all novelelectrolyte features are provided by the unique composition of the acidconcentrates. In this manner, the standard base (bicarbonate)concentrates currently in use with commercial dialysis machines can beused without alterations. However, in one possible embodiment, thephosphate could be provided as part of the base concentrate, toeliminate concerns about incompatibility with Ca²⁺ and Mg²⁺ ions in theacid concentrate.

1. Base Concentrate with Phosphate:

The most important design feature here is the need to provide thephosphate as a mixture of its disodium and monosodium salts in a ratiothat results in the same buffered pH as the pH of a solution prepared bydissolving just sodium-bicarbonate in water. The target pH value isdefined as pH=(pKa1+pKa2)/2, where pKa1 and pKa2 are the aciddissociation constants of carbonic acid at 25 C and the ionic strengthof the concentrate (expected about 6.4 and 10.3 with the target pHaround 8.4). The ratio of the sodium phosphate salts can be derived fromthe equation pH=pKa2+log(salt/acid), where pKa2 is now the second aciddissociation constant of phosphoric acid, about 7.1 at 25 C. Therefore,the ratio of the salt (disodium-phosphate) to acid (monosodiumphosphate) will be about 20:1. The exact ratio may be different slightly(the pKas may be slightly different at the ionic strength of theconcentrate) and can be easily determined experimentally. Such fluiddesign ensures that excessive CO₂ gas, or conversely CO3²⁻ iongeneration does not occur in the bicarbonate/phosphate combinedconcentrate. The concentrate will be provided so that the 1× bicarbonatecan vary between 20 to 40 mmol/L depending on the dilution. Thephosphate will be 1.25 mmol when the bicarbonate is 30 and will varyfrom 0.8 to about 1.7 mmol/L with the dilution of the concentrate.

Base Concentrate with Phosphate:

Base concentrate with phosphate contribution 1X base fluid 1Xbase fluidafter mixing with the acid component component concentrate and water to1X mmol/L mEq/L Sodium 32.44 32.44 HCO3— 30 30 H2PO4(−):HPO4(2−) 1.25*2.44 in 1:20 ratioBase Concentrate without Phosphate:

Base concentrate after mixing 1X base fluid 1Xbase fluid with the acidconcentrate component component and water to 1X mmol/L mEq/L Sodium 3030 HCO3— 30 30Acid Concentrates with Phosphate Dedicated to the Various OperationalModes:

The most important novel features are the low sodium, calcium andmagnesium and the added citrate and phosphate content (whereapplicable). These fluids also assume the use of the sodium chloridesupplemented citrate anticoagulant solutions. About 25%+/− range is alsocontemplated for all of these novel component concentrations. The 1×sodium concentration is approximate and will be clinically variable asallowed by the sodium-modeling program (standard feature of moderndialysis machines) to suit the individual patient and the selectedtreatment modality. The final 1× therapy fluids could also betheoretically provided as bagged sterile fluids and the compositions forsuch use are also contemplated herein.

Acid concentrate with phosphate dedicated to simultaneous pre- andpost-dilution CVVH:

Replacement fluid acid concentrate with phosphate components after 1Xfinal fluid 1X acid fluid mixing with the base concentrate composition;component; and water to 1X mmol/L mEq/L Sodium 136 106 Potassium 4.0 4.0Chloride 110 110 Bicarbonate 30 0 Calcium 0 0 Magnesium 0 0 Phosphoricacid 1.25 1.25 Dextrose 5.5 5.5

Acid concentrate with phosphate dedicated to 12-24-hour SLEDD: (only ifnear complete removal of calcium and citrate from the circuit blood isfound to be clinically detrimental)

Dialysis fluid acid concentrate with phosphate components after 1X finalfluid 1X acid fluid mixing with the base concentrate composition;component; and water to 1X mmol/L mEq/L Sodium 139 111 Potassium 4.0 4.0Acid and basic citrate 1:2 0.9 2.7 Chloride 114.1 114.1 Bicarbonate 28 0Calcium 0.3 0.6 Magnesium 0.15 0.3 Phosphoric acid 1.25 1.25 Dextrose5.5 5.5

The calcium can range from 0.0 mM to 0.8 mM and magnesium from 0.0 mM to0.4 mM (magnesium is about 40-50% of calcium usually). Acid citrate canvary from 0.0 mM to 1.5 mM and total citrate from 0.5 to 3.0 mM. Allsuch variations of the above fluid are fully contemplated according tothe present invention. All other ion concentrations can change by about+−10% and all such variations are also contemplated herein.

Single, compromise acid concentrate with phosphate for all online CRRT:

Therapy fluid acid concentrate with phosphate components after 1X finalfluid 1X acid fluid mixing with the base concentrate composition;component; and water to 1X mmol/L mEq/L Sodium 138 108 Potassium 4.0 4.0Chloride 114 114 Bicarbonate 28 0 Calcium 0 0 Magnesium 0 0 Phosphoricacid 1.25 1.25 Dextrose 5.5 5.5

The calcium can range from 0.0 mM to 0.8 mM and magnesium from 0.0 mM to0.4 mM (magnesium is about 40-50% of calcium usually). Acid citrate canvary from 0.0 mM to 1.5 mM and total citrate from 0.5 to 3.0 mM. Allsuch variations of the above fluid are fully contemplated according tothe present invention. All other ion concentrations can change by about+−10% and all such variations are also contemplated herein.

Single, compromise acid concentrate without phosphate for all outpatientintensive blood purification therapies including pre- and post-dilutionHVHF and regular HD and post dilution HDF:

Dialysis fluid acid concentrate 1X final fluid 1X acid fluid componentsafter mixing with the composition; component; base concentrate and waterto 1X mmol/L mEq/L Sodium 136 99 Potassium 2.0 or 3.0 2.0 or 3.0 or 4.0or 4.0 Acetic acid 3.0 3.0 Chloride 101 or 102 101 or 102 or 103 or 102Bicarbonate 37 0 Calcium 0.0 0.0 Magnesium 0.0 0.0 Dextrose 5.5 5.5

The greatest concern with high blood flows is systemic citrateaccumulation. Therefore, there is no citrate in the above fluids andacetate is used for acidification (to prevent bacterial growth). Theacetate content is comparable to standard acid concentrates in clinicaluse but could be reduced markedly at 1× dilution if desired for a nearlyacetate free therapy fluid and such alterations are fully contemplatedaccording to the present invention. At blood flows above 300 ml, currentfilter technology will limit the plasma citrate and calcium extractionto 60-80% in a single pass. In alternative embodiments, the calcium canrange from 0.0 mM to 1.0 mM and magnesium from 0.0 mM to 0.5 mM(magnesium is about 40-50% of calcium usually). Acid citrate can varyfrom 0.0 mM to 1.5 mM and total citrate from 0.5 to 3.0 mM. All suchvariations of the above fluid are contemplated herein. All other ionconcentrations can change by about +−10% and all such variations arealso fully contemplated. Finally, potassium (K) concentration can be 2,3, or 4 mM in any of the above 1× therapy fluids.

Specifically, the sodium at the standard 34× dilution may be targeted toabout 130 mM by providing the low or zero calcium and magnesium acidconcentrates with about 3-5% less electrolyte content (with preservingthe above molar ratios) for safety monitoring purposes (particularlywhen hypertonic sodium is present in the modified citrate anticoagulant)and this method is provided according to the present invention. Thefinal conductivity of the dialysate at usual dilution ratios then wouldbe about 12.6, about 10% less than the usual 14.0 due to the lowersodium and absent calcium and magnesium, allowing the machine to detectthrough fresh dialysate conductivity monitoring (done routinely on alldialysis machines) that a calcium and magnesium free acid concentrate isbeing used. When the operator confirms the use of the special acidconcentrate for RCA, the acid concentrate dilution ratio could beautomatically adjusted to yield a final fluid with about 134-138 mMsodium as required by the treatment prescription. The only drawback tothis method is that high sodium profiling may be mildly limited with theuse of such acid concentrates.

The 1× fluid compositions are provided above. These values may still beslightly modified based on clinical experience. The machine will varythe dilution of the concentrates depending on the treatment prescriptionto best suit the individual patient. This will result in a range ofconcentrations of the electrolytes in the final ready to use onlinegenerated fluid.

When needed, the phosphate can be provided in the acid concentrateinstead as well in an acid form to hinder bacterial growth. Phosphatemay be omitted from the acid and base concentrates specifically designedfor short, intense, 3-6-hour, 3-times-per-week therapy. When phosphoricacid is not used, acidity of the acid concentrate is ensured by theinclusion of citric acid or acetic acid. In the absence of calcium andmagnesium, salt fouling of the fluid circuits is very unlikely andacidification mainly serves to prevent bacterial growth in the acidconcentrate. The citrate and sodium content is correlated with theoperational mode and the expected composition and rate of infusion ofthe anticoagulant solution. The lower sodium, calcium and magnesiumcontent results in lower conductivity at standard dilution ratios,allowing the machine to detect the presence of the unusual acidconcentrate for RCA, an important safety feature.

When a predominantly diffusive mode of blood purification is employedduring CRRT, (pre-dilution HDF or SLED), calcium and magnesium may haveto be present in the fresh therapy fluid (albeit at reducedconcentrations), to avoid the complete decalcification of the blood thatmight have untoward physiologic consequences (this possible untowardeffect is speculative as no clinical protocols to date have achievedsuch high fractional citrate and calcium extraction in theextracorporeal circuit and is in fact not expected to occur).

Concentrations shown are the contributions to the final 1× combinedconcentrate from Part 1 (Acid) and Part 2 (Base). Depending on therelative flow of fluids from the concentrate Part 1 and Part 2 (machineand online fluid generation system design dependent), the exactcomposition design of the Part 1 and Part 2 concentrates can naturallybe defined exactly to yield the desired final diluted summary 1×product. Such calculations and final concentrate compositions areapparent to those skilled in the art from the usual practice of onlinefluid generation and from the target concentration ranges to be reachedin the final 1× fluid as described above, and are contemplated accordingto the present invention.

The physical design of RCA system 110 and the fluid compositions(anticoagulant, calcium plus magnesium infusion, separate acid and baseconcentrates) according to the present invention allow for theindependent and flexible selection of anticoagulation intensity (theamount of citrate infused into a liter of plasma), calcium and magnesiuminfusion rate, therapy fluid sodium and potassium concentration andtherapy fluid bicarbonate concentration. Detailed knowledge of themovement of the key small solutes in the patient's body and in theextracorporeal circuit during RCA allows automatic, precise mass balancecalculations for all solutes during the use of any treatment operationalmode. This permits the selection of fluid flow rates and therapy fluidcomposition best suited for the individual prescription. The solutefluxes may be inferred from the prescription and fluid compositions aswell as verified/adjusted based on the online clearance measurements.

Online hematocrit sensor 150 and OCM 170 provide for continuous safetymonitoring of the performance of system 110. The OCM 170 allows formathematical precision in clearance dosing, in calcium dosing, inpredicting citrate accumulation and in calculating the diffusive versusconvective component of the blood purification important for medicationdosing and research purposes. The hematocrit sensor 150 may also detectaccess recirculation. Finally, subsequent measurement of onlineclearance with the anticoagulant infusion bolus based method and thetraditional dialysate conductivity modeling based method, whencorrelated with the measured access recirculation, may allow the onlinemonitoring of the patients cardiac output with clinically usefulaccuracy when a permanent (arterial) access is used.

The software control module according to the present invention mayinclude elements to verify proper circuit tubing connections and mayguide the selection of safe citrate prescriptions by the operator. As asafety measure, prescriptions that entail the possibility of citrateaccumulation or other complications may not be allowed. This isdescribed in detail below in the flow steps for RCA system 110.

Operational modes that may be supported include: 1) Purely convectiveRRT with simultaneous pre-dilution and post-dilution hemofiltration forboth 24-hour CVVH and intensive 4-5 hour HVHF therapy (FIGS. 8 a and 8b); 2) Purely diffusive RRT with only net ultrafiltration for both24-hour SLED and conventional 4-5 hour IHD (FIGS. 5 a and 5 b); 3)Post-dilution hemofiltration (online post-HDF) for outpatient 4-5 hourtherapy with high blood flows and a desire to maximize clearance andcontrol cost (FIGS. 7 a and 7 b); 4) Pre-dilution hemofiltration (onlinepre-HDF or CVVHDF) for 24-hour CRRT with a desire to deliver bothconvective and diffusive clearance and minimize clotting (FIGS. 6 a and6 b); 5) Optional single needle operational mode for all extendedtherapy (CRRT or nocturnal therapy) modalities. The greatest benefit ofthis mode is that it ensures that blood withdrawal from the patient isimmediately halted if an access needle disconnection occurs. Incontrast, when two needles are used, in the case of a venous accessdisconnection, there is a potential for a catastrophic bleed as themachine may keep aspirating blood through the arterial needle.

For each of these modalities with appropriate prescriptions, the plasmasmall solute clearance can be calculated and verified periodically witha novel online conductivity dialysance method according to the presentinvention. Assuming access recirculation is monitored and measured bythe hematocrit sensors 150, 152, the whole blood clearance for soluteslike urea can also be inferred from the data. This will provide theclinician with unprecedented flexibility and precision in the selectionof the small solute hourly clearance goal as well as the degree ofconvective versus diffusive blood purification. Control programsderiving the prescriptions for each operational mode are developedallowing for complete automation of the prescription writing. The totaltherapy fluid flow will usually not exceed 250% of the total plasma flowor about 160% of the total blood flow regardless of the purificationmethod used. Such fluid efficiency is fully comparable with what isachieved with current traditional clinical dialysis prescriptions.

Fundamentals of the RCA prescription according to the present inventionare as follows. Sufficient plasma total calcium to citrate ratio must beachieved for effective anticoagulation. The total Ca (mM) to citrate(mM) ratio may range between 2 to 4 in the extracorporeal circuit. Partof the citrate may be provided as acid citrate in the anticoagulantinfusion (to further enhance anti-coagulation through acidification ofthrombin and other coagulation cascade proteins and increase theultrafilterable fraction of calcium by disrupting its binding toalbumin). The plasma flow may be monitored online with a hematocrit andblood flow sensor module 150, 152. This will allow the calculation ofthe delivered calcium load into the circuit and will define thenecessary anticoagulant infusion rate. Access recirculation may also bemonitored by the hematocrit sensor 150, 152.

The prescription should eliminate the possibility of citrateaccumulation even in the complete absence of liver metabolism (liverfailure). This may be achieved by keeping the citrate plasma dialysanceabove 60-80% of the plasma flow in the extracorporeal circuit andcorrelating it with the amount of citrate infused into a liter ofcircuit plasma and the citrate concentration in the therapy fluid used.The target plasma total calcium level should be defined (usually 2-2.5mmol/L depending on the serum albumin concentration) by the operator.This will have an indirect impact on the systemic plasma ionized Cacontent in steady state. The ultrafilterable and dialyzable fraction oftotal calcium should be selected (this will range from 0.7 to 0.95depending of the calcium to citrate ratio, albumin level and pH in thecircuit). The plasma albumin level may be further considered as it willimpact the systemic ionized Ca level at the targeted total systemicplasma Ca level. The systemic citrate level will have minimal impact,even in ICU patients with liver failure, because citrate accumulationbeyond 2 to 3 mM levels cannot occur when filter performance ismaintained at the specified fluid flow rates. Prescriptions and therapyfluid compositions may be provided that allow exact mass balancecalculations for citrate, calcium and magnesium, sodium and bicarbonate(and trace metal minerals).

In the following description, a glossary of the abbreviations used is asfollows:

Csys: calculated steady state systemic plasma citrate concentration in apatient with zero citrate metabolism (liver failure; worst case scenarioin RCA)E: apparent circuit post-anticoagulant infusion arterial plasma citrateto therapy fluid citrate concentration difference reduction ratio duringa single filter pass (“plasma citrate extraction ratio”); (ECit, ECa)DCit: apparent citrate plasma dialysance (DCit* when expressed for theadjusted QBCit during calculations and DCit when expressed for theunadjusted QP)DCond: apparent “summary conductivity solute” whole blood dialysance.This value may be predicted from filter KoACond, Qb, Qd, and Quf and/ordetermined by the sodium citrate bolus based measurement or by thetraditional online conductivity dialysance measurement method (for highblood flow treatment sessions; this latter method is not discussed herebeing prior art and not applicable in SLED)QB: the effective arterial blood water flow for the solute analyzed;QBCond is closely equal to the arterial whole blood water flow forconductivity and QBCit is closely equal to arterial blood plasma waterflow for citrate. In the case of citrate, for the calculation of “E” theplasma water volume is adjusted for the free water shift between theRBCs and the plasma space in response to the hypertonic citrateanticoagulant and DCit* is calculated with these adjustments. OnceE=DCit*/QBCit (=DCit/QP) is derived, the unadjusted QP and DCit can beused to simplify the subsequent calculation of Csys.QP: The arterial blood plasma flow without adjustment for the effects ofthe hypertonic anticoagulant infusion (These shifts are accounted forduring the calculation of E).Cinf: The increase in the arterial plasma citrate concentration as aresult of the anticoagulant infusion, before any pre-filter replacementfluid infusion or adjustment for water shifts between blood fluidcompartments. (These shifts are accounted for during the calculation ofE).Hgb: hemoglobin concentration in the arterial bloodQpre: pre-filter replacement fluid flow rateQpost: post filter replacement fluid flow rateQd: dialysis fluid flow rateQuf: net ultrafiltration (negative fluid balance goal plus the citrateand Ca infusion rates)QCa/Mg: the flow rate of the calcium and magnesium infusionQtf: total therapy fluid flow rate (=Qd in SLED)DCond: “conductivity solute” dialysance determined by the sodium citratebolus based measurementDCit: the calculated citrate dialysance (DCit* when expressed for theadjusted QBCit during calculations and DCit when expressed for theunadjusted QP)Ddiff: the calculated diffusive component of the measured totaldialysance (DdiffCond, DdiffCit); in SLED the diffusive dialysance isequal to the total dialysanceKoA: mass transfer area coefficient; measure of filter performancespecific to solute (KoACond, KoACit)a and S: solute diffusivity and sieving coefficients; aCond; aCit,SCond; SCit,f: correction factor to derive the dialyzable/filterable fraction of thetotal plasma Ca

For the control program for RCA system 110, the flow steps may include:

1) Start Machine in RCA Mode

2)

a) Select Treatment Type: Sustained Low-Efficiency Dialysis (SLED),Hemodiafiltration (pre-HDF or post-HDF), or Pure hemofiltration(pre-CVVH or Pre-post-CVVH).

b) Select Treatment Duration: 10-hour or 24-hour.

c) Select Access Connection: Regular versus Single-Needle.

3)

a) Machine advises filter, tubing, anticoagulant and calcium solutionsand RCA acid concentrate.

b) Confirm all disposables are as advised by the machine.

c) Connect tubing to dialyzer.

d) Connect infusion pumps.

e) Prime system with priming solution.

f) Test system integrity (current machine protocol).

4) RCA priming checks: performed with the circuit arterial and venousends connected in recirculation mode.

a) Confirm conductivity of therapy fluid is at target with RCA Modespecific lesser dilution of the acid concentrate.

b) Alarm if conductivity is abnormal: inappropriate acid concentrate forRCA treatment.

c) Confirm citrate infusion loading onto the citrate pump by turning onthe citrate pump and measuring the increase in conductivity in the draincircuit of the dialyzer.

d) Alarm: it is not the citrate infusion solution that is loaded ontothe citrate pump based on effluent conductivity changes.

e) Confirm calcium infusion loading onto the calcium pump by turning onthe calcium pump and measuring the increase in conductivity in the draincircuit of the dialyzer.

f) Alarm: it is not the calcium infusion solution that is loaded ontothe Ca²⁺-pump based on effluent conductivity changes.

5) Input Patient Information.

a) Sex, height, age, weight (minimum data is weight) (if Watson volumeand V_(E) calculations are desired).

b) Minimum data is systemic hemoglobin and albumin concentration.

6) Select SLED, HDF, or HF For SLED:

7) Treatment information advised by software based on prior selections.

a) Confirm: Filter type (determines expected KoACond, KoACit, SCond,SCit).

b) Input: Maximal access blood flow rate expected (QB).

c) Confirm: Dialysate fluid flow rate (HD and HDF 200% QB; CVVH 200%QP).

d) Input: Total net ultrafiltration desired per treatment (during 10 or24 hours).

e) Confirm: Set dialysis machine alarm parameters.

f) Confirm: Type of citrate anticoagulant solution (ICU versus OPD;likely uniform).

g) Confirm: Type of calcium solution (ICU versus OPD, likely uniform).

h) Confirm: Maximum citrate level in systemic blood allowed (2.0-4.0mM).

i) Confirm: Dialysis acid and base concentrates used.

8) Connect the patient9) Safety checks after initial patient connection in isolated HD mode.

a) Start treatment, confirm citrate infusing in the arterial limb bywatching the effluent conductivity.

b) Measure access recirculation with automated online hemodilution ortemperature technique.

c) Measure baseline in vivo KoACond at QB 150-300 and QD 300-600(ml/min) in 12-hour SLED.

d) Compare with expected value for selected specific filter; alertoperator if significant difference.

e) Calculate baseline in vivo KoACit from the above measurement

f) Measure baseline in vivo KoACond at QB (priming solution) 75-150 andQD 150-300 (ml/min) in 24-hour SLED.

g) Compare with expected value for selected specific filter; alertoperator if significant difference.

h) Calculate baseline in vivo KoACit from the above measurement (in the12-hour mode both dialysate bolus based and blood bolus based DCond willbe measured).

10) Display Confirmation Alarms.

a) Alarm if more than 10-15% recirculation is detected; the treatmentwill still be safe, but less effective for uremic clearance.

b) Measure Hgb concentration with the online sensor (Alarm if more than20% different from initially provided value).

c) Alarm if citrate not on arterial limb of circuit (confirm duringbolus).

d) Alarm if filter Dcond more than 10-20% different from expected invivo value and possibly refuse the filter.

e) Alarm if the expected and the detected replacement fluid conductivityvalues at the RCA Mode dilution of the hyponatric RCA acid concentratedo not match.

11) Analyze input data.

a) Determine prescription and machine settings with in vivo DCond.

b) Display machine generated QB, Cinf, Qd Quf, QCit1, QCa/Mg.

c) Display expected DCond (ml/min) (if using weight-adjustedprescribing).

d) Display expected maximum Csys.

e) Display expected Ca replacement infusion dose (mmol/hour) for circuitCa²⁺ losses (prescriptions can have uniform QB and DCond versus weightadjusted).

For HDF:

7) Treatment Information advised by software based on prior selections.

a) Input: Dialyzer type (determines expected KoACond, KoACit, SCond,SCit).

b) Input: Maximum hemoconcentration allowed in the circuit (define inthe range 50-60%).

c) Input: Therapy fluid summary flow rate (200% of QB).

d) Input: Total clearance goal for CRRT (DCond based Kt/V or just Kt).

d) Input: Total net ultrafiltration desired per treatment (or over 24hours).

f) Input: Set dialysis machine alarm parameters.

g) Input: Type of citrate solution (ICU versus OPD; likely uniform).

h) Input: Type of calcium solution (ICU versus OPD, likely uniform).

i) Input: Maximum citrate level in systemic blood allowed (2.0-4.0 mM).

j) Input: Dialysis acid and base concentrates used.

8) Connect the patient9) Safety checks after initial patient connection in isolated HD mode.

a) Start treatment, confirm citrate infusing in the arterial limb bywatching the effluent conductivity.

b) Measure access recirculation with online hemodilution technique.

c) Measure baseline in vivo KoACond at QB 150-300 and QD 300-600(ml/min) in 12-hour SLED.

d) Compare with expected value for selected specific filter; alertoperator if significant difference.

e) Calculate baseline in vivo KoACit from the above measurement.

f) Measure baseline in vivo KoACond at QB (priming solution) 75-150 andQD 150-300 (ml/min) in 24-hour SLED.

g) Compare with expected value for selected specific filter; alertoperator if significant difference.

h) Calculate baseline in vivo KoACit from the above measurement (in the12-hour mode both dialysate bolus based and blood bolus based DCond willbe measured).

10) Display Confirmation Alarms.

a) Alarm if more than 10-15% recirculation is detected; the treatmentwill still be safe, but less effective for uremic clearance.

b) Measure Hgb concentration with the online sensor (Alarm if more than20% different from initially provided value).

c) Alarm if citrate not on arterial limb of circuit (confirm duringbolus).

d) Alarm if filter Dcond more than 10-20% different from expected invivo value (and possibly refuse the filter).

e) Alarm if the expected and the detected replacement fluid conductivityvalues at the RCA Mode dilution of the hyponatric RCA acid concentratedo not match.

11) Analyze input data and change to HDF operational mode.

a) Determine post-dilution possible as % of QB with sethemoconcentration limit.

b) If CRRT, always use pre-HDF, Qpre 30% of QB and the rest of thetherapy fluid as QD.

c) If short therapy, use post-HDF with Qpost 20% of QB ifhemoconcentration limit allows.

d) Otherwise, use pre-HDF for short therapy as well with Qpre 30% of QB.

e) Determine prescription and machine settings based on treatment goals,patient data and the blood bolus based DCond and if available thedialysate bolus based DCond values.

f) Display QB, Cinf, Qpre (pre-HDF) or Qpost (post-HDF), Quf, QCit1,QCa/Mg.

g) Display expected total DCond (ml/min).

h) Display expected maximum Csys.

i) Display expected circuit Ca loss (mmol/hour) before replacementinfusion (prescriptions can have uniform QB and DCond versus weightadjusted).

For HF:

7) Treatment Information advised by software based on prior selections.

a) Input: Dialyzer type (determines expected KoACond, KoACit, SCond,SCit).

b) Input: Maximum hemoconcentration allowed in the circuit (define inthe range 50-60%).

c) Input: Therapy fluid summary flow rate (150% of QB).

d) Input: Total clearance goal for CVVH (DCond based Kt/V or just Kt).

e) Input: Total net ultrafiltration desired per treatment (or over 24hours).

f) Input: Set dialysis machine alarm parameters.

g) Input: Type of citrate solution (ICU versus OPD; likely uniform).

h) Input: Type of calcium solution (ICU versus OPD, likely uniform).

i) Input: Maximum citrate level in systemic blood allowed (2.0-3.0 mM).

j) Input: Dialysis acid and base concentrates used.

8) Connect the patient9) Safety checks after initial patient connection in isolated HD mode.

a) Start treatment, confirm citrate infusing in the arterial limb bywatching the effluent conductivity.

b) Measure access recirculation with online hemodilution technique.

c) Measure baseline in vivo KoACond at QB 150-300 and QD 300-600(ml/min) in 12-hour SLED.

d) Compare with expected value for selected specific filter; alertoperator if significant difference.

e) Calculate baseline in vivo KoACit from the above measurement.

f) Measure baseline in vivo KoACond at QB (priming solution) 75-150 andQD 150-300 (ml/min) in 24-hour SLED.

g) Compare with expected value for selected specific filter; alertoperator if significant difference.

h) Calculate baseline in vivo KoACit from the above measurement (in the12-hour mode both dialysate bolus based and blood bolus based DCond willbe measured).

10) Display Confirmation Alarms.

a) Alarm if more than 10-15% recirculation is detected; the treatmentwill still be safe, but less effective for uremic clearance.

b) Measure Hgb concentration with the online sensor (Alarm if more than20% different from initially provided value).

c) Alarm if citrate not on arterial limb of circuit (confirm duringbolus).

d) Alarm if filter Dcond more than 10-20% different from expected invivo value (and possibly refuse the filter).

e) Alarm if the expected and the detected replacement fluid conductivityvalues at the RCA Mode dilution of the hyponatric RCA acid concentratedo not match.

11) Analyze input data.

a) Determine post-dilution possible as % of QB with sethemoconcentration limit.

b) Determine prescription and machine settings based on treatment goals,patient data and the blood bolus based DCond and if available thedialysate bolus based DCond values.

c) Program Qpost for the above maximum post-filtration, minus(Qcit1+QCa/Mg+Quf) for maximum citrate clearance with a given QB andtotal Qtf. The Qpre is Qtf (150% of QB)−Qpost.

d) Determine prescription and machine settings.

e) Display QB, Cinf, Qpre and Qpost, Quf, Qcit1, QCa/Mg.

f) Display expected DCond (ml/min) and expected maximum Csys.

g) Display expected circuit Ca loss (mmol/hour) before replacementinfusion (prescriptions can have uniform QB and DCond versus weightadjusted).

For All Operational Modes: 12) Calcium Dosing.

a) DCit is essentially equal to DCa*f correction for dialyzable fraction(0.95 to 0.8 depending on albumin level and Cinf).

b) Target systemic plasma total Ca (mM) is defined: Use Csys (0.25 mMCa/1 mM citrate), systemic albumin (0.2 mM Ca/1 g/dL) and targetsystemic ionized Ca (target Cai=1.00 mM when systemic citrate is assumedto be equal to Csys=3).

c) Circuit Ca loss in steady state is equal to DCa*(Target systemictotal Ca−Catf), where Catf is the calcium concentration in the freshtherapy fluid (mM).

d) QCa/Mg is easily calculated from the circuit Ca loss and Caconcentration of the Ca infusion solution.

e) At start, the operator may have to give 1-4 amps of Ca-gluconate over1-2 hours to bring the systemic ionized Ca close to 1.25-1.5.

13) Continuous safety check.

a) Citrate solution is properly on the citrate pump and arterial limb isarterial (expected constant step-up in effluent conductivity frombaseline Ctf conductivity) (Alarm if citrate bag changed to calcium orsaline or access connection reversed during operation based on effluentconductivity monitoring with all the above IV fluids having differentconductivity).

b) Input Ctf constant in RCA Mode when proper, unique RCA acid andstandard base concentrates are used (Alarm if non-RCA acid concentrateis being supplied at any time).

c) Input: Online measured total Dcond from standard operation andestimated Cp (Alarm if filter performance is declining to prompt bolusclearance interrogation and/or filter change).

d) Input: Measured access blood flow rate: current (QB) (Alarm: when QBis changed because of access issues recalculate all pump speeds andfluid flows).

e) Input: Measured hemoglobin concentration (Alarm: when changed by morethan 10% alert operator to possible bleeding or over-ultrafiltration;recalculate prescription, recommend to operator CBC check, netultrafiltration target revision).

14) Hourly safety check: input data.

a) Input: online measured total Dcond (blood bolus based and whenpossible dialysate bolus based methods both.

b) Input: Measured circuit blood flow rate: current (QB).

c) Input: Set therapy fluid flow rate (usually 150-200% of QB).

d) Input: Measured hemoglobin concentration.

e) Input: Set total net ultrafiltration.

15) Recalculation of the prescription.

a) Calculate: DdiffCond, KoACond, KoACit, DdiffCit, Total DCit.

b) Calculate the maximum possible citrate in systemic blood (Csys;2.0-4.0 mM).

c) Alarm if Csys more than 3 mM and address as follows: Change filter ifKoACit is >than 40-60% less than target for filter. Reduce Cinf iffilter performance is within limits (or increase filter size).Re-measure clearance and recalculate Csys until calculated Csys<=4 mM.

d) Display current clearance after all changes: DCond (in ml/min).

e) Adjust QB, QD, Qcit, QCa/Mg, NetUf, and Qpre and or Qpost asapplicable.

16) Other alarms.

a) Citrate bag is about to run out: (if the machine measures bag weightor knows bag volume and logs new bag setups).

b) Calcium bag is about to run out: (if the machine measures bag weightor knows bag volume and logs new bag setups).

c) RCA acid concentrate is about to run out: (if the machine measuresthe acid concentrate reservoir weight).

d) The treatment goal (total time or total clearance or total net UF hasbeen reached): in 12-hour treatments.

RCA system 110 may contain an online sensor system (OSS) for measuringcalcium, magnesium and citrate in the ultrafiltrate. The same flow stepsdetailed above apply to such a system, except that data from the OSS maybe used to adjust the calcium infusion according to systemic citrate andcalcium levels. As explained herein, the calcium, magnesium and citratevalues measured from the ultrafiltrate by the OSS can be used toback-calculate the values in the patient's plasma. As also explained,the kinetic curve of systemic plasma citrate concentration can be usedto derive the exact value of the liver clearance of citrate as well asthe volume of distribution of citrate, V_(E). Using the aboveparameters, systemic citrate levels can be accurately predicted at anyfuture T time point. The calcium and citrate pump as well as the entireprescription including the therapy fluid bicarbonate concentration (whenflexible) can then be completely controlled by the machine software.

Filter performance can be monitored both by conductivity as well ascitrate clearance measurements. The direct citrate clearancemeasurements again enable complete precision in calcium and citratedosing. Since calcium exits through the hemofilter almost entirely asCa-citrate complex, the measured citrate dialysance will be nearly equalto the total calcium dialysance. The slightly lower Ca-dialysance willbe due to the Gibbs-Donnan effect and the minimal albumin-bound Ca inthe circuit (about 5-20% depending on the amount of citrate infused inthe arterial limb of the circuit, the acidity of the citrate infusionand the plasma albumin level). At any point where blood bolus basedconductivity dialysance is measured, blood bolus based citratedialysance will also be measured simultaneously with the OSS whenavailable on the machine.

Turning now to another aspect of the present invention, home nocturnaldialysis is a re-discovered, expanding method of RRT. Most expertsbelieve that it is the best method of RRT, resulting in excellent uremicand blood pressure control, freedom from most dietary restrictionsotherwise mandatory for ESRD patients on 3 times-per-week dialysis, andresulting in fewer hospitalizations, lesser use of phosphate binders andmost importantly better quality of life. Nevertheless, only a minutefraction of ESRD patients are currently on nocturnal dialysis.

The most important reasons for the limited use of nocturnal dialysisinclude the following. Highly effective anticoagulation is mandatoryduring 8-12-hour treatments to prevent clotting of the extracorporealcircuit and associated alarms and sleep disruption. The only agent incommon use, heparin, has significant side effects and a systemicbleeding risk that increases with higher doses. In addition, singleneedle operational mode is preferred to lessen the risk of majorbleeding in the event of permanent access disconnection. This againrequires powerful anticoagulation. Complex online dialysis fluidgeneration systems are expensive to deploy and maintain in the home, andonline clearance measurements that could be used to monitor efficacy andcompliance have not been widely adapted to slow nocturnal dialysis.Furthermore, RCA has not been developed for home treatments. Stillfurther, biofilm formation and bacterial contamination of components ofthe dialysis system is a major concern, and costs must not exceedmarkedly the overall costs of 3 times weekly in-center dialysis.

According to the present invention, an RCA home system 210 (FIGS. 17a-17 d) may be designed as an RRT device that also doubles to deliverautomated RCA for home nocturnal dialysis. One purpose of the presentinvention is to provide a device that can deliver previouslyunprecedented high convective or diffusive clearances and can beoperated by laypersons in home settings without the need for highlycomplex treatment protocols. RCA home system 210 is a modified versionof the RCA system 110 that is specifically re-designed for the uniquechallenges of home RRT. Therefore, components of system 210 that aresimilar to components of system 110 are identified with like referencenumerals except for the substitution of a “2” prefix.

RCA home system 210 according to the present invention may include acombination of various CRRT and dialysis machine hardware componentsarranged in a unique design, two special modes of operation of thedevice (simultaneous pre- and post-dilution hemofiltration andcontinuous sustained low efficiency dialysis (c-SLED)), and a softwarecontrol module. System 210 may also include a sensor module 256 tomeasure citrate, calcium and magnesium levels online to ensure themaximum accuracy, fluid efficiency and safety of treatmentprescriptions. System 210 may use a novel replacement fluid concentrate,a novel citrate anticoagulant, and novel single premixed calcium plusmagnesium infusion which were designed to fully exploit the system'scapabilities. RCA home system 210 may resemble a traditionalhemodialysis machine and can be constructed from hemodialysis machinecomponents except for online citrate sensor 256 as described below. Mostelements have been discussed above with reference to the RCA system 110of the present invention.

RCA home system 210 can safely provide at least up to 12 liters per hourof convective clearance to patients without relying on the liver tometabolize citrate. The system design prevents citrate accumulation inthe patient, while maintaining highly efficient anticoagulation of theextracorporeal circuit 212. A control program may be used to derive asafe treatment prescription according to treatment goals selected by theoperator. An online citrate sensor 256 may be used to eliminate the riskof citrate accumulation (that may occur only with declining filterperformance in SLED mode) and doubles as an online delivered clearanceand liver metabolic function monitor.

System 210 according to the present invention is shown in FIGS. 17 a and17 b for a machine capable of pre- and post-dilution CVVH for maximalfluid efficiency and in FIGS. 17 c and 17 d for an even simpler machinethat performs only pre-dilution CVVH or SLED depending on the tubingconnection. The common features with RCA system 110 are either notrepeated or repeated only briefly herein. The most important differencesand novel elements are detailed below.

RCA home system 210 may include a single, sterile bag 280 (e.g., 5 literplastic) that may contain a novel, single component, about 30-50×electrolyte concentrate. The hemofiltration replacement fluid may bediluted from this concentrate by mixing it with ultrapure watergenerated by a water treatment module of the RCA online system 210. Theonline fluid generation follows well-established design from currentlyexisting dialysis machines. However, instead of the traditional twobags, system 210 according to the present invention requires only oneconcentrate chamber or bag 280 that contains all electrolytes necessaryexcept calcium and magnesium. This is a major departure from currentfluid mixing systems. The single concentrate reduces complexity of thefluid circuit and makes the dilution procedure very precise and safewith conductivity monitoring of the ready-to-use replacement fluid asthe established safety check for the degree of dilution. Sinceday-to-day flexibility in therapy fluid sodium and bicarbonateconcentration is not needed in home nocturnal dialysis programs, thissimplicity of fluid generation has no significant clinical drawbacks.Individual prescriptions can still be attained if the manufacturerprovides several individual single-component concentrates withmoderately variable final potassium, bicarbonate, and possibly phosphatecontents. The appropriate concentrate can be selected for the patientabout once monthly, similar to the selection of peritoneal dialysisfluid composition and prescription for patients on peritoneal dialysis.

RCA home system 210 may include two highly precise volumetric infusionpumps 234, 244 which may have dedicated air in line detectors and lineclamps (not shown), optionally color-coded and with special tubing todeliver the citrate anticoagulant and the calcium plus magnesiuminfusions as described below with reference to FIGS. 9-16. Infusionlines 228, 242 may have special end connections that will only attach tothe appropriate solution bags 232, 246 and at the other end will bewelded to the entry points in extracorporeal circuit 212 to minimize therisk of disconnection from the circuit 212 and wrong connection ofinfusate bags 232, 246. Pumps 234, 244 may be designed to accept onlythe right type of infusate tubing and may be fully coordinated with theoperation of blood pump 222 and other fluid pumps. This again preventsaccidental connection of the wrong infusate in the wrong place and alsoensures that citrate and calcium plus magnesium infusions are stoppedwhen the machine blood pump 222 and/or replacement fluid pump 264 arenot operating. In addition, the fluid bags 232, 246 may be manufacturedto be significantly different in weight and size as well as in the colorof the plastic and/or legend to further reduce the chance of accidentalwrong connection.

RCA home system 210 may utilize Doppler-based fluid flow and hematocritmonitors or alternatively optical hematocrit sensors 250, 252 on thearterial and venous blood lines 214, 218 as well as possibly on thereplacement fluid line 228 and effluent fluid line 224 for maximalprecision in ensuring that the set blood flow rate on blood pump 222matches the actual blood flow delivered by the action of the blood pump222 and all other fluid flows (pre-filter fluid flow, effluent flow,venous blood flow and net ultrafiltration amount) are all the same asdefined by the machine settings. All crystalloid fluid pumps may bevolumetric for precise control of fluid flow rates.

An online citrate, calcium and magnesium sensor 256 may be provided inthe effluent fluid line 224. This sensor array 256 allows for thederivation of the citrate, calcium and magnesium level in the patient'ssystemic blood. In one safe operational mode of RCA home system 210(more than 66% citrate extraction), citrate accumulation can only occurif the filter performance declines. Laboratory testing is not availablein the home setting. For maximum safety, the indirect data from theonline conductivity clearance monitor may not be sufficient in the homesetting. However, the online citrate and calcium sensor 256 may warn ofany change in systemic citrate and calcium levels in real time andprompt the patient and or the remote monitoring personnel to review andadjust the treatment settings to ensure the safe continuation of the RRTtreatment. Sensor 256 may also serve as an online clearance module, mayprovide information for the fine-tuning of the calcium plus magnesiumdosing and monitor the metabolic function of the liver.

RCA home system 210 may include disposable, sterile fluid circuits whichmay include the replacement fluid and effluent fluid balancing chambers262 of the RRT machine 260. While the ultrapure dialysate generationmodule is not sterile, starting with a sterile concentrate will greatlyreduce the risk of bacterial contamination in the final dialysate. Waterfrom this module and also the generated replacement fluid may passthrough low flux sterilizing filters 282 with pore size small enough toprevent the passage of whole bacteria or endotoxins and pyrogens derivedfrom bacteria. If the implementation of the disposable sterile balancingchamber 262 is too costly, the fresh online replacement fluid may befilter sterilized after passing through the usual, non-disposable, fixedbalancing chamber. The filter sterilization may be necessary to allowdirect infusion of the online replacement fluid into the RRT circuitblood space. These concerns are less pronounced in the nocturnal SLEDdiffusive operational mode of the device, where the online fluid remainsseparated from the blood space by the membrane of hemofilter 216.Specially designed dialysis catheters, access needles, circuit tubingand connectors may also be utilized as described elsewhere herein.Single needle operational mode is as previously discussed for RCA system110.

The elements of the CRRT machine 260 include, but are not limited to,hemofilter 216, usual fluid and blood circuit tubes, conductivitymonitors, fluid heating element, blood leak detector, and air detectorsas used on conventional RRT machines. RCA home system 210 according tothe present invention further includes an operational mode of pre- andpost-dilution CVVH, marked isolated pre-dilution CVVH or SLED with asingle, online generated calcium and magnesium free fluid to maximizesingle pass citrate (and coincident calcium) extraction on the filter216. Initially, the RCA online system-controlled concentrated citrateinfusion may reduce ionized calcium in the systemic blood entering thearterial limb 214 of the extracorporeal circuit 212. This blood may thenbe diluted with the essentially calcium-free pre-filter fluid. Theoriginal hematocrit, blood volume and electrolyte composition may thenbe restored by ultrafiltration on the hemofilter 216 except that theblood leaving the filter 216 will have a 50-75% reduced total calciumand magnesium as well as uremic solute content (the actual reduction isprecisely determined by the treatment settings) and a low ionizedcalcium level preventing blood clotting. Finally, before the blood isreturned to the patient, the RCA online system-controlled calcium plusmagnesium infusion restores normal total calcium and magnesium levels.This procedure will usually be performed with blood flows in the rangeof 150-300 ml/minute during 8-12-hour nocturnal CVVH or SLED.

As described above, RCA home system 210 may utilize an essentiallycalcium and magnesium free pre-filter online-generated replacementfluid. The online fluid generation is simpler and safer since all theremaining electrolytes including phosphate and bicarbonate can now becombined into a single concentrate bag 280 making the fluid generationsystem safer and simpler. An integrated IV pump 244 may be provided toadminister a premixed calcium plus magnesium containing infusion. System210 may control this pump 244 to deliver the supplemental calcium andmagnesium in a fixed ratio in coordination with the RRT prescription andmonthly patient chemistry values. A novel dosing program may be used todrive the pump 244. The online calcium and citrate sensor 256 may alarmif a machine failure or calcium plus magnesium line disconnection was tocause hypocalcemia (or hypercalcemia if too much infusion is given).

In accordance with the present invention, a combination of tri-sodiumcitrate and acid citrate in the pre-dilution fluid may be implementedwith the fluid conductivity further manipulated by the addition ofsodium chloride for safety monitoring purposes. The present inventionfurther contemplates a mandatory addition of phosphate to the pre-filterreplacement fluid (or dialysis fluid) concentrates. This eliminates theneed for monitoring serum phosphate levels and for separate intravenousphosphate administration. Phosphate losses can be very large and canquickly lead to severe hypophosphatemia with high daily (nocturnal)clearance goals unless the phosphate is provided in the replacementfluid. Since calcium and magnesium are essentially not present in theRRT fluid concentrate, phosphate can be added commercially, preservingphysiologic phosphate levels in the therapy fluid and consequently inthe patient. Finally, phosphate is also a calcium chelator and mayresult in a further minor reduction in the ionized calcium level in thecircuit. If stored in a single compartment with bicarbonate, phosphatemay be provided in a pH-adjusted buffered form to avoid the possibilityof CO₂ gas or carbonate generation by reacting with bicarbonate.

Integrated online hematocrit sensors 250, 252 may be provided straddlingthe pre-dilution fluid connection 230 on the arterial limb 214 of theblood circuit 212. The online hematocrit sensors 250, 252 allowminute-to-minute calculation of the plasma volume in the blood flowinginto the circuit 212. This ensures the most accurate and possiblycontinuously adjusted dosing of citrate to achieve the target citrate toplasma calcium ratio. Another benefit of the hematocrit sensor 250, 252is that it can be utilized for periodic automated monitoring forcatheter recirculation using an induced hemodilution-based technique.This allows the correction of measured clearances for accessrecirculation when this phenomenon is present. Detecting recirculationin the access early is important to ensure full exposure of the circuitto uremic blood from the patient and in correctly performing clearancecalculations using the OSS. Further, in a method according to thepresent invention, the described online hematocrit sensor pair 250, 252can also be used to derive the delivered blood flow in the arterial limb214 of the circuit 212 by analyzing the hemodilution induced by theinfusion of a known amount of pre-filter replacement fluid. Thepre-filter fluid may be delivered by existing highly accurate volumetricpumping technology. The observed hemodilution in response to a knownamount of pre-filter fluid infusion will allow the precise backcalculation of the delivered blood flow that was diluted in thisfashion. Finally, the hematocrit sensor 250, 252 as a blood volumemonitor may detect blood volume contraction in the patient due toexcessive ultrafiltration and may alert the patient and stop the netfluid removal before resultant hemodynamic compromise could develop.

RCA home system 210 may further include integrated Doppler sensors tomonitor fluid flow rates in the arterial blood line 214, venous bloodline 218, pre-filter fluid line 228, and effluent fluid line 224. Thesefluid flows are predetermined by the settings of the machine. Withmodern machine technology using precise volumetric pumps on thecrystalloid fluid lines (but using a non occlusive roller pump as usualon the blood line to avoid hemolysis) and the generally lower flow ratesutilized during CRRT, clinically significant, more than 10% deviationsfrom the preset flow rates are unlikely. The machine 260 has multiplesafeguards against deviations from the prescribed fluid flow rates.These include the balancing chamber 262 for correlating the effluent andthe replacement fluid flows, the duplicate hematocrit sensors 250, 252to monitor delivered blood flow as well as the ratio of delivered bloodflow to pre-filter fluid flow, and finally the Doppler sensor system.The simultaneous use of all of these measures ensure the safe operationof RCA home system 210 according to the present invention that utilizesa strict coordination of the flow rates of the various fluids itutilizes. Finally, continuous, precise monitoring of the patient'ssystemic citrate and calcium levels through the composition of theeffluent fluid will provide yet another, ultimate level of safety forthe procedure.

Effluent line 224 of RCA home system 210 may contain an OSS that canindirectly monitor the systemic concentration of citrate, calcium andmagnesium. This module can analyze the ultrafiltrate and derive thepatient's plasma citrate and total calcium and magnesium levelcontinuously with mathematical precision and display it in real time.The OSS may alarm when dangerously rising citrate levels or abnormal(low or high) total calcium levels are detected. Measuring citrate mayalso serve as a basis for a novel online clearance module, filterpatency monitor and liver function monitor. The concepts used toimplement the citrate sensor 256 are also applicable to otherultrafilterable solutes. Monitoring of sodium, glucose, pH, bicarbonateand CO₂ as well as any ultrafilterable small solute level is alsopossible.

The design, fluids, and control program of the RCA home system 210eliminate all of the risks of RCA as described below. RCA home system210 may include all of the safety features of RCA System 110 asdiscussed herein. The modifications of home system 210, most notably thesingle-chamber concentrate 280 and the OSS will address additional risksunique to the home treatment environment as follows:

1) Metabolic alkalosis: The baseline acid-base chemistry is expected tobe normal in stable home patients. The therapy fluid bicarbonate of25-40 may be selected about once monthly and will depend on the weeklyequivalent clearance delivered, baseline liver function and endogenousacid generation rate (protein nutrition). The single chamber concentrate280 will reduce complexity and will prevent erroneous bicarbonate orsodium settings by the operator as these will be largely fixed with asingle concentrate.2) Metabolic acidosis: see above for metabolic alkalosis.3) Hypocalcemia 1 (due to net calcium loss from the patient): Theultrafiltrate total calcium and magnesium losses are preciselycalculable in the RCA home system 210. The online total calcium sensormodule 256 may be necessary for catastrophic system failures (forexample, disconnection or leakage of the calcium plus magnesiumreplacement infusion) in the home. This sensor module will remove allconcerns related to calcium, magnesium and citrate levels in thepatient's plasma. This module will eliminate the need for laboratorymonitoring of the patient's systemic total and ionized calcium andmagnesium levels during RCA. The fundamental principle of the sensor 256is simultaneous determination of free ionized calcium, free ionizedmagnesium and free ionized citrate levels in the effluent fluid of thecircuit. This allows for the mathematical derivation of the totalcalcium content of the effluent fluid with clinically sufficientaccuracy.4) Hypocalcemia 2 (due to citrate accumulation): Safe prescriptionsprevent citrate accumulation even in the absence of liver metabolism byproviding for a 66-75% citrate extraction on the hemofilter in a singlepass. The OSS will derive the systemic citrate level in real time andwill detect a rise in citrate levels accurately before the systemicionized calcium level could drop by more than 0.25 mmol/L. A kineticprogram may analyze the RRT prescription (fluid compositions and flowrates as well as blood flow rate). It also may utilize anthropometricdata to predict the citrate volume of distribution in the patient. Datafrom the OCM allows filter clearance calculations. Finally, an estimateof the patient's citrate clearance in L/minute may also be derived fromthe measured systemic citrate curve. This will allow the prediction ofthe citrate curve after a prescription change.5) Rebound hypercalcemia (due to release of calcium from citrate afterCVVH is stopped): The RCA home system 210 may not allow home treatmentprescriptions to continue without modification if the patient's detectedsystemic citrate level exceeds 3.0 mmol/L. This will ensure thatsystemic citrate levels stay <=3.0 mM corresponding to about maximum0.75 mM chelated calcium that could be released after RCA is stopped inall patients who can metabolize citrate. (Most patients will have 1 mMplasma citrate and about 0.25 mM Ca chelated by citrate in the steadystate). The RCA protocol may be designed to keep systemic ionized Calevels around 1-1.25 and therefore the highest calcium level after RCAis stopped will be <=1.75 mM and most patients will rebound to 1.25-1.5mM Ca levels after treatment. Utilizing the OSS, the system 210 can alsoprovide a lower citrate and or calcium infusion rate in the last fewhours of the treatment to lower the total systemic citrate and calciumlevels prior to stopping the RRT.6) Hypophosphatemia: Depending on the achieved equivalent weeklyclearance and dietary habits, the single bag concentrate 280 may havevarying amount of phosphate, to suit the individual patient.7) Nursing errors: The RCA home system 210 may be designed to be fullyautomated and provide home nocturnal RRT with citrate anticoagulationwithout any intervention from nurses or other health care personnel.8) Rare: Ionized hypomagnesemia: Magnesium dosing may be fullycoordinated with calcium. The only variable, the molar ratio of calciumto magnesium may be fine tuned in the range of 2:1 to 2:0.5 with moreclinical experience in the future. Similar to the current clinicalpractice of having several acid concentrates with different calcium tomagnesium molar ratios, it is likely that the calcium and magnesiuminfusion according to the present invention will have to be formulatedas two or three distinct varieties with slightly different Ca:Mg molarratios in the above range to accommodate the individual patient.9) Declining filter performance: The conductivity-based OCM as well asthe OSS monitoring the citrate bolus-based online clearance can detectthis complication and alert the operator that the filter needs to bereplaced.10) Trace metal depletion: Cationic trace metal supplementation may beprovided with the calcium infusion to restore precise mass balance forthese trace solutes. Any trace metal incompatible with the calciuminfusion can be provided in the citrate anticoagulant infusion in anadjusted concentration.11) Access disconnection: Needle disconnection can be safely detected ifa single needle operational mode is used in combination with a novelcircuit tubing connector to access a permanent access for dailynocturnal dialysis.12) Wrong connection of citrate, calcium or acid concentrate or bloodcircuit to patient: These errors may be prevented by the hardware designof the system 210 as well as through conductivity monitoring-basedsafety checks.13) Disconnection of the calcium and or citrate infusion: This can becompletely prevented by appropriate circuit tubing design(non-disconnectable, physically continuous infusion to blood lineconnection). The disconnection of the citrate infusion can also bedetected by monitoring the circuit effluent conductivity and or citrateconcentration. As a major improvement, disconnection of the calciuminfusion can now be detected with the OSS through detecting decreasingsystemic calcium levels despite normal functioning of the rest of theRCA home system 210. The optical hematocrit sensors 250, 252 can detectaccess recirculation and can enable the correction of blood bolus-basedclearance measurements as well as the correction of derived systemiccitrate and calcium levels for this phenomenon.

The novel therapy fluid used by the RCA home system 210 is describedbelow. All concentrations and dilutions including, but not limited to,1×, 5×10×, and 50× formulations are fully contemplated in accordancewith the present invention.

Novel Single Pre- and Post-Filter Replacement Fluid (or Dialysate inNocturnal-SLED Mode):

Pre-filter fluid (with 37X 1X fluid 1X fluid dilution used) mmol/L mEq/LSodium 138  138 Potassium 4 4 HCO3— *27  27 Chloride 112.3  112.3Calcium 0 0 Magnesium 0 0 Phosphate   *1.35 *2.7 (HPO4—:H2PO4— = 20:1)Dextrose   5.5 5.5 The most likely concentrate composition is providedabove, wherein values denoted with an * may be slightly modified basedon clinical experience. The manufacturer may modestly vary thepotassium, sodium and bicarbonate content of the concentrate to bestsuit the individual patient. This will result in a range of combinationsof the electrolytes in the final ready to use online generated fluidsimilar to several compositions of peritoneal dialysis bags beingavailable to patients on peritoneal dialysis.The ranges of possibilities in the 1× therapy fluid composition areprovided below:

Therapy fluid 1X (mmol/L) Sodium 130-150 Potassium 2-4 HCO3— 20-40Chloride  90-135 Calcium 0-0 Magnesium 0-0 Phosphate   0-1.5(HPO4—:H2PO4— = 20:1) Dextrose 5.5-11 

The provided concentrate is an important component of RCA home system210 of the present invention. The lower potassium and higher bicarbonateconcentrates are proposed for the few patients who want only every otherday nocturnal therapy. The phosphate may be provided as a tri-basic anddi-basic salt, pH-adjusted to be compatible with bicarbonate and toavoid CO₂ gas generation by virtue of being in the same concentratecontainer. (The zero range for phosphate may only be needed when 3×weekly brief 3-6 hours outpatient treatments are done with the RCA homesystem 210 and fluids).

A novel control program that monitors all sensor data and ensures a safeprescription based on treatment goals, mode of operation (pre- andpost-dilution CVVH versus c-SLED as selected by the operator), andpossibly patient variables input from the sensor devices (OSS) may beutilized according to the present invention. The control module has thecapability to completely automate the safe functioning of the RCA homesystem 210 but is proposed in the default operational mode primarily asa safety and alarm tool with no authority to automatically changetreatment settings (other than stop the machine if needed during analarm).

The control program that may be used by the RCA home system 210 may beessentially identical to the control program of RCA system 110, whereindata from the OSS may be used to adjust the calcium infusion accordingto systemic citrate and calcium levels. When the RCA home system 210 isimplemented as shown in FIGS. 17 a-17 b, the operational modes of pre-and post-dilution CVVH and SLED can be used as discussed for system 110.For the implementations in FIGS. 17 c-17 d, the SLED mode is unchanged;however, CVVH may only be performed in isolated marked (66%)pre-dilution mode. Modified calculations from the pre- andpost-ultrafiltration mode as discussed for RCA system 110 withpost-infusion being zero can still be used. The program simplifies theuse of the device and allows for exact and automated calculation of theprescribed treatment variables including blood flow, citrateanticoagulant infusion rate, pre filter fluid flow, and degree ofdilution of the pre-filter fluid during online generation as well as therate of the calcium plus magnesium supplemental infusion. Once or a fewtimes monthly, the physician may program the treatment modality, theduration and the frequency of the treatments and the hourly clearancegoals and can provide data on measured hemoglobin and albumin levels aswell as the patient's liver function (usual liver clearance) asdetermined from prior treatments.

In the default mode, the program will generate a prescription based on amarkedly high pre-dilution (with or without post-dilution depending onthe system design) with a pre-filter fluid flow to plasma flow ratio of2:1 that will not allow dangerous citrate accumulation in the systemicplasma of the patient even in the absence of liver metabolism. Allpatients can safely reach up to 100-200 ml/kg/hr treatment goals withsuch a prescription. The clearance goal is expressed corrected for thedegree of pre-dilution. More fluid efficient prescriptions that utilizelesser amounts of pre-dilution of the patient's blood in the arteriallimb 214 of the circuit 212 would rely on the liver to clear some of thesystemic citrate. If such prescriptions are allowed, should a sudden andunexpected reduction in liver function occur, the provided citrate andcalcium sensor 256 may detect citrate accumulation and the resultingdanger of ionized hypocalcemia before this complication could develop toa clinically significant degree. The generated alarm may contact theremote monitoring center to warn about the liver function and willtrigger the machine to default to safe treatment parameters.

During the operation of RCA systems 10, 110, 210 according to thepresent invention, the arterial and venous blood flow, as well as thecitrate and calcium infusions are precisely controlled by the systemwithout any intervention from the health care personnel. This designaffords the safe use of special catheter or circuit tubing connectordesigns as shown in FIGS. 9-16. These accessories may replace or connectto standard blood circuit tubing in current clinical use. The specialblood circuits, access catheters or circuit tubing connectors mayintroduce the citrate anticoagulant as early as possible into thearterial blood pathway and reverse the anticoagulant effect by thecalcium infusion into the venous blood pathway as late as possible.These designs are possible as the blood flow as well as the citrate andcalcium infusion flows are now precisely controlled and monitored by thedialysis machine instead of the human operator. The new blood circuitscan come with special end connectors or can be completely integratedwith the citrate and calcium delivery systems.

FIGS. 9 a and 9 b illustrate a triple lumen access catheter 300 having afirst lumen 302 representing an arterial blood withdrawal path, a secondlumen 304 representing a venous blood return path, and a third lumen 306representing an arterial infusion path. Third lumen 306 may be in fluidcommunication with first lumen 302 via an opening 308 in the lumen wallthat allows for injection of an infusion solution. According to oneaspect of the present invention, opening 308 may be provided near theentrance 310 of first lumen 302 used to withdraw blood from the patient,wherein third lumen 306 may have a cap 312 or other closure at that end.The infusion solution may contain the citrate (or other) anticoagulant,and the infusion solution line (not shown) may have an air detector.Catheter 300 allows the introduction of citrate anticoagulant into thearterial blood as early as possible.

FIGS. 10 a and 10 b illustrate a quadruple lumen catheter 314 having afirst lumen 316 representing an arterial blood withdrawal path, a secondlumen 318 representing a venous blood return path, and a third lumen 320representing an arterial infusion path, and a fourth lumen 322representing a venous infusion path. Third lumen 320 may be in fluidcommunication with first lumen 302 via an opening 324 in the lumen wallthat allows for injection of an infusion solution, such as citrateanticoagulant. Fourth lumen 322 may be in fluid communication withsecond lumen 318 via an opening 326 in the lumen wall that allows forinjection of an infusion solution, such a calcium solution. According toone aspect of the preset invention, opening 324 may be provided near theentrance 328 of first lumen 316 used to withdraw blood from the patient,wherein third lumen 320 may have a cap 330 or other closure at that end.Likewise, opening 326 may be provided near the exit 332 of second lumen318 used to return blood to the patient, wherein fourth lumen 322 mayhave a cap 334 or other closure at that end. Therefore, using catheter314 citrate may be infused into the arterial line to immediately provideanticoagulation of the blood entering the extracorporeal circuit. Inorder to provide anticoagulation throughout the entire circuit, calciumwhich reverses citrate anticoagulation, may be infused in the venousreturn line at the last possible location before blood is returned tothe patient. The infusion solution lines (not shown) may have airdetectors.

FIG. 10 c illustrates a quadruple lumen vascular access catheter 314according to another aspect of the present invention which connect toarterial blood line 14, 114, venous blood line 18, 118, citrate infusionline 28, 128 and calcium infusion line 42, 142 which may have differentlengths and/or colors and which may be fused at a fixed point so thatthe circuit 12, 112 may only be connected together in the correctposition. This arrangement ensures that the anticoagulant is alwaysinfused into the arterial line 14, 114 and the venous infusion solutionis always delivered into the venous blood returned to the patient. Theinfusion solution lines 28, 128, 42, 142 may have air detectors (notshown).

As illustrated in FIG. 10 d, quadruple lumen vascular access catheter314 may include connectors 340 of different configurations, such as withthe male and female line connectors reversed and of different colors.The catheter connection ends correspond to connection ends of thecomplementary type for the dialysis arterial and venous blood tubing 14,114, 18, 118 as well as the anticoagulant and calcium infusion lines 28,128, 42, 142. Therefore, the arterial and venous blood ports as well asthe medication infusion ports may all be color-coded and mutuallyincompatible to prevent errors stemming from line reversal or othermisconnection. This ensures that the circuit 12, 112 can only beconnected with the catheter 314 in the correct configuration and thatthe anticoagulant is always infused into the arterial line and thevenous infusion solution is always delivered into the venous bloodreturned to the patient. The infusion solution lines may have airdetectors. The citrate and calcium ports on catheters 300 and 314 mayhave safety valve mechanisms to prevent air aspiration if one or both ofthe infusion lines disconnect, and the blood pump continues to run.Catheter 314 may be designed for short (3-5 hours long) IHD sessionswith RCA where achieving high blood flows and hourly clearance goals isnecessary.

A triple lumen catheter 350 with a single blood path (FIGS. 14 a-14 d)may be used for clinical applications where a high blood flow is notmandatory and a smaller diameter catheter (possibly even in a peripheralvein) may be acceptable. In this catheter 350, blood flow direction isalternating in a single lumen. A central lumen 352 may be used towithdraw blood from the patient during a first, arterial pump cycle,then on the next, venous pump cycle infuse blood back into the patient.A second lumen 354 representing an arterial cycle infusion pathway incommunication with central lumen 352 may be used to infuse citrateanticoagulant or another solution into the incoming blood during thearterial pump cycle. During the venous cycle, a third lumen 356representing a venous cycle infusion pathway in communication withcentral lumen 352 may be used to infuse calcium or another infusion intothe blood before reentry into the circulation. The calcium infusion linemay be clamped during the arterial pump cycle, and the anticoagulantinfusion line may be clamped during the venous pump cycle.

As with catheters 300 and 314, the anticoagulant may be introduced intocentral lumen 352 via an opening 358 in the lumen wall at the tip of thecatheter 350, such that the blood receives anticoagulant at the exactpoint where it enters the extracorporeal circuit. In order to provideanticoagulation throughout the entire circuit, calcium which reversescitrate anticoagulation, may be introduced into central lumen 352 via anopening 360 in the lumen wall at the tip of the catheter 350. Also asabove, second lumen 354 and third lumen 356 may be provided with a cap362 or 364, respectively, or other closure. As shown in FIGS. 14 b and14 d, catheter 350 according to the present invention may accommodateblood tubing and infusion lines with different arterial and venousconnectors.

This smaller catheter 350 may be particularly suited for heart failurepatients who could benefit from 12-24-hour ultrafiltration with RCAusing a peripheral vein access and in whom placement of a large dialysiscatheter for conventional access is difficult to justify because of theassociated risk of complications. Catheter 350 requires a dialysismachine that is capable of the single needle dialysis operational mode(this is an optional module on modern dialysis machines). An additionalbenefit of this symmetrical design is that mixed up connection of thearterial and venous blood lines and/or the citrate and calcium infusionlines cannot result in any clinical complication as long as the temporalcoordination between the blood pumping cycles and the citrate andcalcium pumping cycles is preserved. The asymmetrical connector designsof FIG. 14 d may only be needed if a dedicated RCA blood circuit tubingis used with asymmetrical blood and infusion line end designs.

Permanent accesses (arterio-venous fistulas and grafts) are very rarelyutilized for CRRT because of fears of unnoticed venous access needledisconnection and subsequent catastrophic blood loss in the ICU. Similarconcerns surround the use of permanent accesses in home nocturnaldialysis programs. In a two-needle dialysis session, when the venousneedle disconnects (slips out of the access), the machine may not alarmand can cause massive blood loss with continued arterial pumping. As asolution, the catheter described above (FIGS. 14 a-14 d) can also beimplemented as a circuit tubing connector that attaches to a singleneedle that is inserted into a permanent vascular access (single needledialysis operational mode is required), which may be embodied as aquintuple lumen circuit connector 366 with a single blood path (FIGS. 15a-15 d).

FIGS. 15 a-15 d illustrate a connector 366 (e.g., plastic) according tothe present invention for circuit priming and to attach to a singlevascular access needle from a standard dialysis blood line set andstandard medication infusion lines for use with single needle dialysisoperational mode. The central lumen 368 may be used to withdraw bloodfrom the patient during an arterial pump cycle, then on the next, venouspump cycle infuse blood back into the patient. A needle connection 370may be disposed on one end of central lumen 368. Connector 366 includesan arterial blood port 372 in fluid communication with central lumen 368and arranged to be connected to an arterial blood line, a venous bloodport 374 in fluid communication with central lumen 368 and arranged tobe connected to a venous blood line, an arterial cycle infusion port 376in fluid communication with central lumen 368 and arranged to beconnected to an arterial infusion line for injection an infusion (e.g.,citrate anticoagulant) during the arterial pump cycle, and a venouscycle infusion port 378 in fluid communication with central lumen 368and arranged to be connected to a venous infusion line for injection ofan infusion (e.g., calcium) during the venous pump cycle. Arterial andvenous blood ports 372, 374 and arterial and venous infusion ports 376,378 may branch outwardly from central lumen 368 as shown. In addition,needle connection 370 may be capped for circuit priming.

According to one aspect of the present invention, arterial and venousinfusion ports 376, 378 may be closer to needle connection 370 than arearterial and venous blood ports 372, 374. With this configuration, theblood may receive anticoagulant as it enters the extracorporeal circuit,and may receive calcium as it leaves the circuit to be returned to thepatient. As above, the venous infusion pump may be turned off during thearterial pump cycle, and the citrate infusion pump may be turned offduring the venous pump cycle.

The design of connector 366 has the same benefits as far as mixed upconcoction of blood and/or medication lines are concerned as singlelumen catheter 350 described above. The most important added benefit isthat the connector 366 allows single needle dialysis to be performed ona permanent access. This operational mode is particularly suited forextended therapy sessions (e.g., nocturnal dialysis and CRRT) where ahigh blood flow is not needed, but the risk of a catastrophic bleed fromaccess needle disconnection is greater. In the single needle mode, ifthe needle disconnects, the system may sense air in the arterial limb ofthe circuit with the next arterial (or intake) cycle and may alarmimmediately, essentially eliminating the risk of a major unnoticedbleeding in the event of needle disconnection.

The connectors depicted in FIGS. 15 a-15 b connect to blood lines withsymmetrical ends with the connector of FIG. 15 a accommodating infusionlines with identical ends and the connector of FIG. 15 b accommodatinginfusion lines with asymmetrical ends. The connectors depicted in FIGS.15 c-15 d accommodate a citrate-dedicated blood circuit and connect toblood lines with asymmetrical ends, with the connector of FIG. 15 caccommodating infusion lines with identical ends and the connector ofFIG. 15 d accommodating infusion lines with asymmetrical ends. Finally,these devices may be very useful during the initial circuit priming andsafety check step. All lines can be connected, and the needle connectioncan be attached to a priming solution line to prime and test the system.After testing is complete, the priming line may be removed and theneedle connected.

Special blood circuits, blood circuit connectors, and medicationinfusion lines designed for two-needle or conventional double lumendialysis catheter access treatments with RCA according to the presentinvention are shown in FIGS. 11 a-11 b, 12 a-12 b, 13, and 16 a-16 b.

FIG. 11 a illustrates connectors 380, 382 (e.g., plastic) according tothe present invention which may be used as a kit to attach standarddialysis blood lines (independent arterial and venous blood circuitends) for dialysis using separate arterial and venous needles. Connector380 may be an arterial connector which includes a central lumen 384, aneedle connection 386, and an arterial infusion port 388 for theinfusion of citrate or other anticoagulant at the point where bloodenters the extracorporeal circuit. A similar connector 382, with themale and female connectors reversed, may be a venous connector whichincludes a central lumen 390, a needle connection 392, and a venousinfusion port 394 for the infusion of calcium at the point where bloodis returned to the patient. The orientation of the male and femaleconnectors may be maintained from the beginning to the end of eachinfusion line. As above, the location of the arterial and venousinfusion ports 388, 394 provides anticoagulation throughout the entirecircuit. FIG. 11 a depicts a configuration where the blood ports 396,398 are the same but the infusion ports 388, 394 are different. FIG. 11b depicts both the blood ports 396, 398 and infusion ports 388, 394having different configurations, which may be used to attach acitrate-dedicated dialysis blood tubing (different arterial and venousblood circuit ends).

FIG. 12 a illustrates an arterial infusion line connector 500 accordingto an aspect of the present invention which may be used to attach acitrate-dedicated dialysis arterial blood line using separate arterialand venous needles. Connector 500 includes a central lumen 502, a needleconnection 504, an arterial blood port 506, and an arterial infusionport 508. As shown, arterial infusion port 508 and citrate infusion line28, 128, 228 may be integrated into one unit, preventing accidentalanticoagulant infusion disconnection. Citrate infusion line 28, 128, 228may have a specific key segment 510 configured to be received by citratepump 34, 134, 234 (and not calcium pump), as well as a specific bagconnector 512 configured to be received by the citrate bag (and notcalcium bag). This arrangement provides anticoagulation throughout theentire circuit and ensures that the citrate can only be infused into thearterial limb of the blood circuit.

FIG. 12 b illustrates a venous infusion line connector 514 according toan aspect of the present invention which may be used to attach astandard or citrate-dedicated dialysis venous blood line using separatearterial and venous needles. Connector 514 includes a central lumen 516,a needle connection 518, a venous blood port 520, and a venous infusionport 522. As shown, venous infusion port 522 and calcium infusion line42, 142, 242 may be integrated into one unit, preventing accidentalcalcium infusion disconnection. Calcium infusion line 42, 142, 242 mayhave a specific key segment 524 configured to be received by calciumpump 44, 144, 244 (and not citrate pump), as well as a specific bagconnector 526 configured to be received by the calcium bag (and notcitrate bag). If a citrate dedicated blood tubing is used, the calciumcan only be infused into the venous limb of the blood circuit.

FIG. 13 illustrates citrate-dedicated blood circuit tubing withintegrated arterial and venous medication infusion line connectors 530,532 according to the present invention which is used to connect theextracorporeal circuit to the patient using separate arterial and venousaccess needles or a traditional double lumen hemodialysis catheter. Theadvantages to this configuration are that the connectors 530, 532, bloodlines 14, 114, 214 and 18, 118, 218, and infusion lines 28, 128, 228 and42, 142, 242 are integrated into one unit, preventing accidental citrateor calcium infusion disconnection. Integration of the citrate infusionline 28, 128, 228 with the arterial connector 530 and the calciuminfusion line 42, 142, 242 with the venous connector 532 ensures thatanticoagulant only enters the blood circuit in the arterial limb andcalcium only enters the venous limb.

FIGS. 16 a-16 b illustrate a connector 534 (e.g., plastic) according tothe present invention to attach to a single vascular access needle or toa single lumen catheter from a standard dialysis blood line for use withsingle needle dialysis operational mode. Connector 534 includes acentral lumen 536, needle connection 538, arterial blood port 540,venous blood port 542, arterial infusion port 544, and venous infusionport 546. Arterial infusion port 544 may be integrated with arterialinfusion line 28, 128, 228, and venous infusion port 546 may beintegrated with venous infusion line 42, 142, 242, eliminating thechance of infusion line disconnection. FIG. 16 a depicts arterial andvenous blood ports 540, 542 having the same configuration, and FIG. 16 bdepicts arterial and venous blood ports 540, 542 having differentconfigurations, such as for accommodating citrate-dedicated bloodcircuit ends.

In the above embodiments, the medication infusion lines may be made ofrigid plastic material that minimizes changes in the filling volume ofthe lines with the pumping cycles to guarantee the greatest accuracy ofinfusate delivery. The connection to the citrate or calcium infusionsolution bag should be above the pumping segment and air detectorportions of the IV infusion pumps, so that accidental disconnection fromor emptying of the bag would be detected immediately by detecting air inthe line.

The catheters and connectors according to the present invention whichmay be used for RCA may maximize anticoagulation efficiency and (in thecase of the single needle tubing connector) will allow safe use ofpermanent vascular accesses for 12 to 24 hour CRRT or home nocturnalhemodialysis. The single lumen catheter for RCA may allow the morecommon use of a peripheral vein for isolated UF with RCA for example forvolume overloaded heart failure patients in whom placement of atraditional access catheter may be deemed too aggressive. When highblood flows and hourly clearances are not needed but accidental venousaccess disconnection could be fatal as in CRRT and nocturnal dialysis, atriple lumen RCA catheter or a single needle plastic adapter, each witha single blood pathway and symmetrical or asymmetrical (to accommodateasymmetrical infusion line ends) citrate- and calcium infusionconnections may be used. Proper coordination of the arterial(aspiration) blood pump cycle with activation of the citrate infusionpump and the venous (re-infusion) blood pump cycle with the activationof the calcium infusion pump ensures proper circuit anticoagulation aswell as the reversal of the anticoagulation just when the processedblood is returned into the patient. In the event of accessdisconnection, the machine alarms when a pressure change is detectedand/or air is aspirated into the blood line in the arterial (aspiration)cycles following the disconnection, preventing clinically significantblood loss.

The citrate and the calcium bags may have different and mutuallyincompatible connection locking mechanisms to completely preventinadvertent wrong connection of the bags. In addition, the totalconductivity of the citrate and calcium infusions will be substantiallydifferent. This will help detect wrong connection of the bags throughthe online clearance-monitoring tool or by direct conductivitymeasurements of the infusates themselves. Conductivity monitoring of theanticoagulant infusion line and the calcium plus magnesium infusion lineby any method to detect the presence of inappropriate fluid conductivityand hence inappropriate fluid flowing in these tubing segments is fullycontemplated according to the present invention.

The conductivity-based online clearance monitor according to the presentinvention is now discussed in further detail.

Traditional safety monitoring with laboratory measurements of total andionized calcium and Lytes 7 with anion gap every 6 hours (as in thecurrent clinical protocols in use) is not sufficient for treatments withhigh hourly clearance goals. While traditional laboratory monitoring isinsufficient to ensure the safety of RCA with sigh hourly clearancegoals, such goals are becoming the standard of care and are easilyachieved with online fluid generation at a reasonable cost. However, ifthe prescription is carefully written and the various fluid flows andcompositions are defined appropriately, RCA with high clearance goalswill keep all major electrolyte values in the normal range. The onlyvariable in the system 10, 110, 210 that could often be a cause ofcomplications is the possibly declining filter performance, for examplewith progressive protein fouling of the membrane and/or clotting of thefiber bundle. Therefore, in the absence of a commercially availableonline citrate and/or ionized calcium sensor, online filter clearance(performance) monitoring in conjunction with safe prescriptions may beutilized for patient safety in the implementation of online safetymonitoring for the RCA system 10, 110, 210 according to the presentinvention.

In order to write a safe prescription that prevents systemic citrateaccumulation even in shock-liver (anhepatic) patients, the presentinvention includes a calculation method whereby the maximal systemiccitrate concentration that can develop in the absence of citratemetabolism is calculated for any RRT prescription. The principles ofwriting a safe prescription are explained below. In essence, the maximumpossible systemic citrate level during RCA with a given prescriptionneeds to be calculated. The abbreviations used are as follows:

C_(Cit): the concentration of citrate in the anticoagulant fluidQ_(Cit): the flow rate of the anticoagulant fluidC_(sys): steady state systemic plasma citrate concentration in a patientwith zero citrate metabolismC_(ven): the plasma citrate concentration in the blood circuit venouslimb before the blood is returned to the patientE: apparent circuit post-anticoagulant infusion arterial plasma citrateto therapy fluid citrate concentration difference reduction ratio duringa single filter pass (“plasma citrate extraction ratio”)D_(Cit): apparent citrate plasma dialysance (D_(Cit)* when expressed forthe adjusted QBCit during calculations and D_(Cit) when expressed forthe unadjusted Q_(P))D_(Cond): apparent “summary conductivity solute” whole blood dialysance(this value may be predicted from filter KoA_(Cond), Qb, Qd, Q_(pre),Q_(post) and Q_(uf) and/or determined by the sodium citrate bolus basedmeasurement or by the traditional online conductivity dialysancemeasurement method (for high blood flow treatment sessions))QB: the effective blood flow for the solute analyzed; Q_(BCond) isclosely equal to the arterial whole blood water flow for conductivityand Q_(BCit) is closely equal to arterial blood plasma water flow forcitrate. In the case of citrate, for the calculation of “E” the plasmawater volume is adjusted for the free water shifts between the RBCs andthe plasma space in response to the hypertonic citrate anticoagulant andthe mildly hypotonic pre-filter online therapy fluid infusion (whenapplicable) and D_(Cit)* is also calculated with these adjustments. OnceE=D_(Cit)*/Q_(BCit) (D_(Cit)/Q_(p)) is derived, the unadjusted Q_(P) andD_(Cit) can be used to simplify the subsequent calculation of C_(sys).Q_(P): The arterial blood plasma flow without adjustment for the effectsof the hypertonic anticoagulant infusion (These shifts are accounted forduring the calculation of E).C_(tf): Citrate concentration in the therapy fluidC_(inf): The increase in the arterial plasma citrate concentration as aresult of the anticoagulant infusion, before any pre-filter replacementfluid infusion or adjustment for water shifts between blood fluidcompartments. (These shifts are accounted for during the calculation ofE). C_(inf)=C_(Cit)/(Q_(BCit)/Q_(Cit)).

In the anhepatic patient, there is no systemic citrate metabolism andcitrate clearance is solely through the extracorporeal circuit, whereFIG. 18 illustrates an explanation of the calculation of the maximumpossible systemic citrate level during RCA. In the anhepatic patient,the steady state is reached when C_(sys)=C_(ven). If the variable E isdefined as: E=C_(inf)/((C_(sys)+C_(inf))−C_(tf)) then((C_(sys)+C_(inf))−C_(tf))*(1−E)+C_(tf)=C_(sys) will be true.Rearrangement yields C_(sys)=C_(inf)*(1−E)/E+C_(tf). In the steadystate, the anticoagulant loadQ_(p)*C_(inf)=D_(Cit)*((C_(sys)+C_(inf))−C_(tf)), the plasma watercitrate dialysance multiplied by the citrate concentration gradientbetween the anticoagulated arterial plasma and the therapy fluid.Rearrangement yields D_(Cit)/Q_(p)=(C_(inf)/(C_(sys)+C_(inf)−C_(tf))=E.D_(Cit) can be calculated from D_(Cond); the D_(CondB) (whole bloodconductivity dialysance) is measured by the online clearance module. Theflows Q_(B) and Q_(P) are known. Finally, C_(sys) is calculated from E,C_(tf) and C_(inf).

Therefore, the steady state is reached when the new citrate loaded intothe combined patient and CRRT circuit space is equal to the net citrateremoved from the patient and CRRT circuit combined in the circuiteffluent as shown in Equation 1:

Citrate load=Q _(P) *C _(inf) =D _(Cit)*((C _(sys) +C _(inf))−C_(tf))=Citrate removal  1:

The citrate removal is by definition the apparent plasma citratedialysance multiplied by the citrate concentration gradient. Forsimplicity, after calculating E we use Q_(P) and the apparent plasmaD_(Cit) (instead of QBCit and DCit*) without adjustment for water shiftsbetween blood fluid compartments as these adjustments were made duringthe calculation of E.Rearrangement yields Equation 1*:

(C _(inf)/((C _(sys) +C _(inf))−C _(tf))=D _(Cit) /Q _(P) =E  1*:

D_(Cit)/Q_(P)=D_(Cit)*/Q_(BCit) can be calculated from the measuredtotal D_(Cond) (see below); the D_(Cond) (apparent whole bloodconductivity dialysance) is measured by the online dialysance module andQ_(BCond) and Q_(BCit) are known. When calculating D_(Cit)* fromD_(Cond), the differences in the summary sieving and diffusivitycoefficients for the negatively charged citrate and citrate-Ca orcitrate-Mg complexes (probably slightly above 1) as compared to thesummary sieving and diffusivity coefficients for conductivity (equalto 1) are considered. In general, a low estimate for E can usually becalculated online if the online conductivity dialysance can be measuredduring RRT with RCA with clinically acceptable accuracy (methoddescribed below).

Using the definition of E as: E=(C_(inf)/((C_(sys)+C_(inf))−C_(tf)) andsome rearrangement, Equation 2 will then be true:

((C _(sys) +C _(inf))−C _(tf))*(1−E)+C _(tf) =C _(sys)  2:

Alternatively, in the anhepatic patient, the steady state also meansthat C_(sys)=C_(ven), in other words the venous blood plasma citrateconcentration returning to the patient will be equal to the arterial(systemic) plasma citrate concentration before the infusion of the freshanticoagulant (we ignore the effects of the minimal netultrafiltration). Therefore, Equation 2 again follows with a differentlogic using the initial definition of E:

C _(ven) =C _(sys)=((C _(sys) +C _(inf))−C _(tf))*(1−E)+C _(tf)  2:

Finally, solving Equation 2 for C_(sys) yields Equation 3:

C _(sys) =C _(inf)*(1−E)/E+C _(tf)  3:

A few examples for calculating C_(sys) with Equation 3 are given below.During pre-post-dilution CVVH for CRRT, the maximal practical E will beabout 0.75. If the therapy fluid has no citrate in it, (C_(tf)=0), theneven with very strong anticoagulation with C_(inf)=7.5 mM the C_(sys)will be 2.5 mM or less (less if there is liver metabolism of citrate).If the therapy fluid has citrate with C_(tf)=1.2, then with lesser, butstill strong, anticoagulation with C_(inf)=6 the C_(sys) will be 3.2 mMor less (less if there is liver metabolism of citrate). When using theRCA system 10, 110, 210 according to the present invention, the maximalpractical E may be about 0.66. The C_(inf) can be calculated accordingto its definition and will be 8 mM with the CitrateEasy16 fluid and a 2liter plasma to 1 liter CitrateEasy16 fluid flow ratio. Both thepre-dilution fluid and the post-dilution fluid then can be thought of asreplacement fluids with C_(tf)=0. The maximum C_(sys) will be 4 mM orless (if there is liver metabolism).

During pre-dilution CVVHDF or pure SLED for CRRT, the maximal practicalE will be about 0.85. Even if the therapy fluid has citrate in it,(C_(tf)=1.2) and even with very strong anticoagulation with C_(inf)=7.5the C_(sys) will be 2.7 mM or less (less if there is liver metabolism ofcitrate). If the therapy fluid has no citrate with C_(tf)=0 and evenwith very strong anticoagulation with C_(inf)=7.5 the C_(sys) will be1.5 mM or less (less if there is liver metabolism of citrate).

During high volume pre-post hemofiltration (HVHF), intermittenthemodialysis (IHD) or postHDF with high blood and therapy fluid flowrates, the maximal attainable E can be as low as 0.6-0.7. Under thesecircumstances, the anticoagulation intensity, C_(inf) must be reduced toabout 4-5 mM and C_(tf) should be preferably zero or maximum 0.8 mM.Also, a filter with the highest surface area, flux and resultantcitrateKoA may be utilized. All of these alterations ensure that C_(sys)remains in the 2-3 range even in the absence of liver function (notmentioning the fact that it is unlikely that a patient with no livermetabolism of citrate would be encountered in the outpatient setting).

In summary, in Equation 3 control over all the variables is possible. Byselecting the appropriate citrate pump speed for a given arterial bloodplasma flow, C_(inf) may be defined. By carefully designing the therapyfluid concentrate, C_(tf) may be selected. By using an appropriatefilter and blood flow and therapy fluid flow rates and a database ofD_(Cond) and D_(Cit) values predicted from these variables, E can beprogrammed to the target 0.6-0.9 range, as long as the filterperformance remains unchanged from baseline. This last prerequisite isimportant to the continued safety of the RCA after the start of theprocedure. Finally, a low estimate for E can be monitored online bymonitoring D_(Cond) online and calculating E. The need for online filterperformance monitoring may require that the RCA system 10, 110, 210according to the present invention have an online clearance module thatworks at all blood and therapy fluid flows, including the low flowstypically used for CRRT. The only possible exception may be in theoperational mode of pre- and post-dilution hemofiltration as here theall-convective citrate clearance is highly reliable and is easilycalculated.

The present invention provides a novel online conductivity dialysancemonitor (OCM) for RRT with RCA. A commercially available moduleessentially determines conductivity dialysance by altering theconductivity of the fresh dialysis fluid and measuring the subsequentconductivity change of the spent dialysate (see U.S. Pat. Nos. 6,702,774and 6,939,471). Common to all previous implementations is the concept ofvarying the sodium concentration (and conductivity) of the freshdialysate by about 10% and measuring the reflection of these programmedvariations in the conductivity of the spent dialysate. This approach isnot feasible with the low therapy fluid flow rates of CRRT.

Using the currently available methods, changing the composition of thefresh dialysate takes a very long time at the low dialysate flow ratestypically used for CRRT. The rate of change is related to the ratio ofthe dialysate flow rate (Q_(d)) and the volume of the concentrate mixingchamber and dialysate tubing V_(m), ratio=Q_(d)/V_(m). At the lowdialysate flow rates used in CRRT, the pumping of the dialysate alsobecomes intermittent, causing further difficulties in the measurement.Finally the effects of access-, cardiopulmonary- and systemicrecirculation may all become more pronounced. At the very highfractional plasma clearance rate (K) needed for the safe removal ofcitrate (K>=80% of blood circuit plasma flow (Q_(p))), even largechanges in the fresh dialysate conductivity will cause only modest(<=30% of the change in the fresh fluid), and therefore difficult toprecisely measure changes in the effluent fluid conductivity. Finally,theoretically the KoA (mass transfer area coefficient; a standardizedmeasure of membrane performance) of the membrane could be determined ata conveniently higher Q_(d), using techniques of the current art.However, this KoA would not be the same as the KoA present at the lowQ_(d) values of CRRT because of fluid layering and channeling effectsthat develop at those low flow rates.

The current art does not utilize the possibility of introducing a bolusof concentrated sodium citrate or other conductive solution into thearterial limb 14, 114, 214 of the blood circuit 12, 112, 212.Hemodialysis machines in current clinical use do not have integratedsodium pumps on the blood circuit. However, the citrate pump 34, 134,234 necessary for anticoagulant administration in the RCA system 10,110, 210 according to the present invention may in essence be aconcentrated sodium solution pump and is eminently suited for thepurpose of online conductivity dialysance monitoring. Therefore, in afundamental departure from the practiced art, the present inventionincludes a novel modification of conductivity-based hemofilter clearancemonitoring in which the conductivity dialysance may be determined byusing the concentrated sodium citrate pump 34, 134, 234 to modulate theincoming blood sodium citrate content (and thereby conductivity) bymeans of a small bolus of trisodium citrate infusion (as opposed tomodulating the fresh therapy fluid sodium concentration, which will bekept constant). The effects of such modulation are a precise andimmediate change in the arterial blood plasma sodium citrateconcentration and conductivity, as shown in FIG. 19 for the calculationof the effect of the sodium citrate bolus, and an almost immediatechange in the filter effluent fluid sodium content and conductivity, asshown in FIGS. 20 a-20 b.

In particular, FIG. 19 illustrates a calculation of the conductivity ofplasma (C_(pin)) in the arterial limb of the extracorporeal circuitentering the hemodialyzer. All parameters are known or measured valuesexcept C_(p) and hence C_(pin). FIG. 20 a illustrates an onlineclearance monitor in accordance with the present invention. Aconductivity sensor C1 can be placed in the therapy fluid line beforethe fluid is infused into the filter (into the dialysate and/or theblood compartment). A second conductivity sensor C2 can be placed in theeffluent line of the dialysis machine. Increasing the concentration ofsodium citrate (and possibly sodium chloride or sodium bicarbonate) andhence the conductivity of the blood plasma (C_(pin)) entering thedialyzer for a short period of time (T_(B)=t₂−t₁; bolus method) producesa corresponding response in the sodium concentration and hence theconductivity measured in the effluent, C₂(t). Data from the transientincrease in effluent conductivity can be used to determine the dialyzerconductivity dialysance online. The C₂(t)−C₁(t) (inter-bolus) persistentdifference can also be used for less accurate but truly continuousmonitoring of conductivity dialysance and hence filter performance inbetween boluses. (Differences in C₁(t), C₂(t) and C_(pin)(t) are not toscale). During the positive bolus method, QB may be reduced to keep(QB+Qcit) unchanged.

FIG. 20 b also illustrates an online clearance monitor in accordancewith the present invention. Decreasing the concentration of theanticoagulant sodium citrate (and sodium chloride or sodium bicarbonatepossibly with it) and hence the conductivity of the blood plasma(C_(pin)) entering the dialyzer for a short period of time (T_(B)=t₂−t₁;“negative bolus” method) produces a corresponding response in the sodiumconcentration and hence the conductivity measured in the effluent,C₂(t). Data from the transient decrease in effluent conductivity can beused to determine the dialyzer conductivity dialysance online. TheC₂(t)−C₁(t) difference can also be used for less accurate but trulycontinuous monitoring of filter performance in between boluses.(Differences in C₁(t), C₂(t) and C_(pin)(t) are not to scale). Also,both A_(B) and ΔC_(eff)B are negative values as expected for thenegative bolus method. During the negative bolus method, QB may beincreased to keep (QB+Qcit) unchanged.

The rate of change of the effluent conductivity will be related to theratio Q_(b)/V0, where Qb is the arterial blood flow rate and V_(f) isthe blood filling volume of the filter. This ratio is much larger thanthe Q_(d)/V_(m) mentioned earlier in the description of prior art, andensures that the method will be practical for the low fluid flow ratesprevalent in CRRT prescriptions. The magnitude of the change will berelated to the ratio of Q_(b)/Q_(d) and usually will be about 50-80% ofthe change in the plasma conductivity, allowing precise measurements.Due to the 90-100% fractional extraction of the conductivity bolus inthe CRRT operational mode, cardiopulmonary and systemic recirculation ispredicted to have an insignificant effect on the measurement,particularly if a high-low bolus technique is used. Access recirculationmay have a more marked effect; however, this can be corrected for bymeasuring the degree of recirculation with the hematocrit sensor.Overall, the apparent conductivity dialysance measured by the blood sidebolus and dialysate side sensor method will give a comparably accurateindirect tool to monitor conductivity (and indirectly citrate and urea)dialysance as the prior art. This method, however, will work at very lowQB values and will not result in salt loading of the patient, bothimprovements over prior art.

The following equations show the calculation of the apparentconductivity dialysance for all treatment modalities as measured fromeffluent conductivity changes and the calculation of the target safetyvariable true filter D_(Cit) from the true filter D_(Cond) which, inturn, can be calculated from the measured D_(Cond). These calculationsare performed assuming no access, cardiopulmonary or systemicrecirculation during the novel conductivity dialysance measurementprocedure.

These conductivity dialysance calculations may be expressed for totalblood water flow, since following the infusion of hypertonic citrateinto the plasma space, water and urea will quickly cross red blood cell(RBC) membranes to continuously equilibrate tonicity, osmolality andconductivity between the plasma and RBC space in the extracorporealcircuit. The dialysance calculations for citrate should be expressedwith plasma water flow and plasma water dialysance, also accounting forthe temporary water shifts between the RBC space and the plasma space inresponse to the hypertonic citrate infusion and the hypotonic pre-filterreplacement fluid infusion when used. Q_(B) in this regard is always theeffective blood water flow for the specific solute being investigated.Such prerequisites are apparent to those skilled in the art and suchmodified calculations, while not shown for all possible variations, arealso fully contemplated according to the present invention.

In the first step, the total true filter D_(Cond) is obtained. (Theeffect of access- and cardiopulmonary recirculation on the measurementof conductivity dialysance and the calculation of the true filterD_(Cond) is discussed later.) Next, the diffusive dialysance componentof the total apparent dialysance is calculated (where applicable). Oncethe diffusive dialysance is known, the KoA_(Cond) of the filter can becalculated. The KoA_(cond) is converted to KoA_(Cit) based on the knownconstant diffusivity constants for conductivity and citrate. Using theKoA_(Cit), Q_(BCit) (as adjusted for water shifts between the fluidspaces of whole blood and the pre-filter replacement fluid flow) andQ_(D), the diffusive component of the total apparent D_(Cit)* iscalculated. Finally, the total D_(Cit)* is derived by adding theconvective dialysance component (when applicable) to the diffusivecomponent calculated earlier. Once D_(Cit)* is known, E_(Cit) andmaximum C_(sys) can be determined as shown herein regarding writing asafe prescription for RCA.

The terms used in the equations are defined below:QB: effective arterial blood water flow (Q_(BCond), Q_(Bcit), adjustedarterial blood plasma water flow for citrate)Hgb: hemoglobin concentration in the arterial bloodQ_(P): arterial plasma flowC_(p): “conductivity solute” concentration in the plasma water enteringthe filter without citrate infusionC_(pin)(1): “conductivity solute” concentration in the plasma enteringthe filter with normal citrate infusion rateC_(pin)(t): “conductivity solute” concentration in the plasma enteringthe filter during the citrate bolus at “t” time pointC_(pin)(S): “conductivity solute” concentration in the plasma enteringthe filter during the citrate bolusC_(Cit): “conductivity solute” concentration in the citrateanticoagulantQ_(Cit)(1): flow rate of the citrate anticoagulant during normalconditionsQ_(Cit)(B): flow rate of the citrate anticoagulant during the temporarysodium citrate bolusQ_(pre): pre-filter substitution fluid flow rateQ_(post): post-filter substitution fluid flow rateQ_(d): dialysis fluid flow rateQ_(s): total substitution fluid flow rateQ_(uf): net ultrafiltration (negative fluid balance goal plus thecitrate and Ca infusion rates)Q_(tf): total therapy fluid flow rate (=Q_(d)+Q_(s))C_(eff)(1): “conductivity solute” concentration of the effluent fluidduring baseline citrate anticoagulation conditionsC_(eff)(2): “conductivity solute” concentration of the effluent fluidduring the temporary sodium citrate bolus at “t” time pointA_(B): the total amount of increased “conductivity or solute” appearingin the effluent in response to the sodium citrate bolus delivered by theanticoagulant pumpT_(B): the exact duration of the citrate pump running faster to deliverthe citrate bolusDC_(eff)(B): the time averaged effluent “conductivity solute”concentration increase during the citrate bolusC_(eff)(B): the time averaged effluent “conductivity solute”concentration during the citrate bolusC_(tf): “conductivity solute” concentration of the fresh therapy fluidD_(Cond): “conductivity solute” dialysance determined by the sodiumcitrate bolus based measurementD_(Cit): the calculated citrate dialysance (D_(Cit)* when expressed forthe adjusted Q_(BCit) during calculations and D_(Cit) when expressed forthe unadjusted Q_(P))D_(diff): the calculated diffusive component of the measured totaldialysance (D_(diffCond), D_(diffCit))KoA: mass transfer area coefficient; measure of filter performancespecific to solute (KoA_(Cond), KoA_(Cit))

S: summary solute sieving coefficient S_(Cond), S_(Cit)

a: summary solute diffusivity coefficient (Gibbs-Donnan factor;a_(Cond); a_(Cit))

The summary conductivity of the blood and the fresh and spent therapyfluids is essentially provided by sodium ions with their accompanyingsmall solute (chloride, bicarbonate, phosphate and citrate) anions.Equation (1) defines the apparent conductivity dialysance under baselineoperating conditions (modified from published art):

$\begin{matrix}{D_{cond} = {( {{Qd} + {Qs} + {Quf}} )\frac{( {{{Ceff}\; 1} - {Ctf}} )}{a_{cond}( {{{Cpin}\; 1} - {Ctf}} )}}} & (1)\end{matrix}$

To largely reduce the effect of the unknown Cp (affecting Cpin1) in thecalculation, the bolus method may be used. For greatest accuracy (asallowed by the precision of the blood pump), during the citrate bolusthe total filter blood water flow, Q_(b)+Q_(Cit(B)) is kept constant bytemporarily decreasing the Q_(B) by the bolus to baseline anticoagulantinfusion rate difference (QcitB-Qcit1) (about 1-5% decrease over thebaseline Q_(B) depending on how concentrated the anticoagulant solutionis) and the Q_(tf) is kept unchanged. Under such conditions, theD_(Cond) will remain practically constant during the bolus.

When the citrate bolus is given, the effluent conductivity as a functionof time, C_(eff)(t) will first rise and then fall as shown in FIG. 20 a.(A negative bolus method implemented by reducing the citrate infusion asshown in FIG. 20 b is also possible). Integrating the change inconductivity from baseline (C_(eff)(t)−C_(eff)(1)) by dt from the timepoint, t₁ at the start of the bolus to the time point, t₃ after thebolus when the effluent conductivity returns to baseline, and thendividing it by the duration of the citrate bolus infusion, T_(B) yieldsthe time averaged increase of effluent conductivity over baselinecorresponding to the bolus, DC_(eff)B. Adding this value to C_(eff(1))yields the time averaged effluent conductivity during the citrate bolus,C_(eff(B)).

By defining C_(eff(B)) in this manner, Equation (2) is true after alldata is collected from the bolus:

$\begin{matrix}{D_{cond} = {( {{Qd} + {Qs} + {Quf}} )\frac{( {{CeffB} - {Ctf}} )}{a_{cond}( {{CpinB} - {{Cpin}\; 1}} )}}} & (2)\end{matrix}$

It is known that a_(Cond) is equal to 1 when the “hypothetical summarysolute” conductivity is being studied. Equations (1) and (2) can berearranged and combined to eliminate C_(tf); the result is Equation (3):

$\begin{matrix}{D_{cond} = {( {{Qd} + {Qs} + {Quf}} )\frac{( {{CeffB} - {{Ceff}\; 1}} )}{a_{cond}( {{CpinB} - {{Cpin}\; 1}} )}}} & (3)\end{matrix}$

In Equation (3), all variables are either set on the machine (Q_(d),Q_(s) and Q_(uf)) or are measured and calculated (C_(eff)B, C_(eff)1).The denominator (C_(pi1)B−C_(pin)1) can be calculated (ignoring thetemporary and fully reversing osmotic water shifts between the red bloodcell volume and the plasma volume of the blood in response to thehypertonic sodium citrate anticoagulant infusion and subsequenthypotonic therapy fluid exposure) as follows from Equations (4), (5) and(6) (see FIGS. 19, 20 a, and 20 b):

$\begin{matrix}{{{Cpin}\; 1} = \frac{( {{Qb} \cdot {Cp}} ) + ( {{Qcit}\; {1 \cdot {Ccit}}} )}{( {{Qb} + {{Qcit}\; 1}} )}} & (4)\end{matrix}$

Similarly, Equation (5) when lowering QB during the bolus as discussedabove:

$\begin{matrix}{{CpinB} = \frac{ {( {{Qb} - {QCitB} + {{Qcit}\; 1}} ) \cdot {Cp}} ) + ( {{QcitB} \cdot {Ccit}} )}{( {{Qb} + {{Qcit}\; 1}} )}} & (5)\end{matrix}$

Using Equations (4) and (5) to express (C_(pin)B−C_(pin)1), afterrearrangement yields Equation (6):

$\begin{matrix}{( {{CpinB} - {{Cpin}\; 1}} ) = \frac{( {{QcitB} - {{Qcit}\; 1}} )( {{Ccit} - {Cp}} )}{( {{Qb} + {{Qcit}\; 1}} )}} & (6)\end{matrix}$

In Equation (6), all variables are known except C_(p). However, sincethe electrolyte composition and therefore the conductivity of the humanplasma is strictly regulated, in one approach C_(p) is assumedapproximately equal to 14 mS+−1.5 mS. The relative error range thisassumption introduces into the calculation will depend on the value ofC_(cit). If the C_(Cit) value is very large (highly concentrated citratesolution with additional sodium chloride or sodium bicarbonate (550 mMor higher sodium content), the error introduced by the estimated Cp willbe ±1-3% at most. Such errors will be further reduced as the treatmentreturns the patient's plasma electrolyte composition towards normal in afew hours and C_(p) approximates the normal 14 mS. In a second solutionto the problem of C_(p) being unknown, D_(Cond) is first calculatedusing the assumed value of C_(p) as described above in Equation (6) andthen (3). The calculated D_(Cond) is then inserted into Equation (1) andEquation (1) is solved for C_(pin)1. Subsequently, C_(pin)1 is insertedinto Equation (4) and Equation (4) is solved for C_(p). The so derivedC_(p) is then re-inserted into Equation (6) and Equation (6) isre-solved for (C_(pin)B−C_(pin)1). This value is then re-inserted intoEquation (3) to recalculate the D_(Cond). These steps may be performedrecursively by a computing module until the individual final values forD_(Cond) and C_(p) are approximated within 0.1%. Finally, a thirdvariation of the technique is contemplated, during which conductivity isalso measured on the arterial and venous blood lines without directphysical contact with the blood or compromising sterility. This allowsfor maximal precision of the clearance measurements, but requires somenovel detection elements.

Using the value obtained from Equation (6) it is now possible to solveEquation (3) and derive the value of D_(Cond). The D_(Cond) valueobtained for conductivity dialysance can be converted into bloodclearance values for urea and other small solutes, taking into accounthow the Gibbs-Donnan effect may influence the movement of negativeversus positive ions as compared to the neutral, non-ionic solute ureaor the summary charge neutral “hypothetical summary conductivitysolute”. Once the apparent or total, D_(Cond) conductivity dialysance isknown, it is possible to calculate the diffusive dialysance,D_(diffCond) component as described in prior art and published in theliterature (however, the effect of any access recirculation if presentmust be removed first, as discussed below).

For any solute during intermittent hemodialysis with some netultrafiltration (Q_(uf)) and during post-dilution hemodiafiltration withQ_(post) replacement fluid rate and Q_(uf) net ultrafiltration, D_(diff)is derived by using Equation (7) (where we assume QB is the effectiveblood water flow for the specific solute and the solute specific sievingcoefficient, S is used):

$\begin{matrix}{{D_{diff}({postHDF})} = {({Qb})\frac{D_{Total} - {S( {{Qpost} + {Quf}} )}}{{Qb} - {S( {{Qpost} + {Quf}} )}}}} & (7)\end{matrix}$

For any solute during pre-dilution hemofiltration with Q_(pre)replacement fluid rate and Q_(uf) net ultrafiltration, D_(diff) isderived by using Equation (8) (where we again assume QB is the effectiveblood water flow for the specific solute corrected for the effects ofwater shifts between the RBC and plasma space and the infusion of thepre-filter replacement fluid and we use the solute specific sievingcoefficient, S:

$\begin{matrix}{{D_{diff}{preHDF}} = {( {{Qb} + {Qpre}} )\frac{( {{\frac{( {{Qb} + {Qpre}} )}{Qb}D_{total}} - {S( {{Qpre} + {Quf}} )}} )}{( {{Qb} + {Qpre} - {S( {{Qpre} + {Quf}} )}} }}} & (8)\end{matrix}$

Equation (8) can be deduced from Equation (7) if one considerspre-dilution hemofiltration to be a special case of simple dialysis withnet ultrafiltration where the new Q_(b)* is equal to Q_(b)+Q_(pre), thepre-dilution corrected D_(Total)* is equal toD_(Total)·((Q_(b)+Q_(pre))/Q_(p)) and net ultrafiltration becomesQ_(pre)+Q_(uf). In the special case of simultaneous pre- andpost-dilution hemofiltration, when Q_(d)=0 and the solute sievingcoefficient is S, Equation (3) still applies:

D _(Total)=(Q _(pre) +Q _(post) +Q _(uf))·((C _(eff) B−C _(eff)1)/(S·(C_(pin) B−C _(pin)1)))

Since this operational mode involves no dialysis, D_(diff) is zero andis not calculated, and D_(Total) can also be expressed as:

D _(Total) =S·(Q _(pre) +Q _(post) +Q _(uf))·(Q _(b)/(Q _(b) +Q _(pre)))

From this:

D _(TotalCit) =D _(TotalCond)*(S _(Cit) /S _(Cond))*(Q _(P) /Q _(B))*((Q_(B) +Q _(Pre))/(Q _(P) +Q _(Pre)))

From these equations, it is apparent that a decline of the small soluteapparent dialysance is unlikely in pure convective renal replacementtherapy as long as the target total ultrafiltration ofQ_(pre)+Q_(post)+Q_(uf) is achieved, unless S changes markedly, which isnot probable due to the highly predictable nature of small solutemovement with purely convective blood purification. Dialysance forindividual solutes is calculated by knowing their S sieving coefficientsand the total ultrafiltration rate. (The apparent S value may changemodestly for electrically charged solutes depending on the ratio of thepre-dilution (Q_(pre)) and post-dilution (Q_(post)) replacement fluidflow rates and this may have to be considered in the electrolyte massbalance calculations when selecting the therapy fluid composition forvarious ratios of Q_(pre) and Q_(post) fluid flows.)

Once the D_(diffCond) has been determined from the total D_(Cond)measured at a given (effective) Q_(b) and Q_(d), the KoACond of thefilter membrane can be calculated as published in the literature, (seeEquations (9.1) and (9.2)) and can be compared to the expected valueprovided by the filter manufacturer and/or established in vivo by localuser experience.

In pure dialysis and post-dilution HDF, Equation (9.1):

$\begin{matrix}{{KoACond} = {( \frac{{Qb} \cdot {Qd}}{( {{Qb} - {Qd}} )} ) \cdot {\ln ( \frac{{Qd}( {{Qb} - {Ddiff}} )}{({Qb})( {{Qd} - {Ddiff}} )} )}}} & (9.1)\end{matrix}$

In pre-dilution HDF, Equation (9.2):

$\begin{matrix}{{KoACond} = {( \frac{({QbQpre}){Qd}}{( {{Qb} + {Qpre} - {Qd}} )} ) \cdot {\ln ( \frac{{Qd}( {{Qb} + {Qpre} - {Ddiff}} )}{( {{Qb} + {Qpre}} )( {{Qd} - {Ddiff}} )} )}}} & (9.2)\end{matrix}$

The KoACond changes measured as a function of time while keeping thetherapy parameters unchanged for any given filter will allow thedetection of declining filter performance and impending clotting. TheKoACond is converted to KoACit as shown in Equation (9.3):

$\begin{matrix}{{KoACit} = \frac{{KoACond} \cdot a_{Cit}}{a_{Cond}}} & (9.3)\end{matrix}$

Knowing the KoACit allows the calculation of the DdiffCit from theeffective Q_(BCit) for citrate and the Qpre and Qd fluid flow ratesprescribed, as shown in Equations (10.1) and (10.2). In pure dialysisand post dilution HDF, Equation (10.1) is used where QB now denotesQ_(BCit) and KoA denotes KoACit:

$\begin{matrix}{{D_{diff}{Cit}} = {{QBCit}\frac{^{{KoA}\frac{({{Qd} - {Qb}})}{({{Qd} \cdot {Qb}})}} - 1}{^{{KoA}\frac{({{Qd} - {Qb}})}{({{Qd} \cdot {Qb}})}} - \frac{Qb}{Qd}}}} & (10.1)\end{matrix}$

In pre-dilution HDF, Equation (10.2) is used where QB now denotesQ_(BCit) and KoA denotes KoACit:

$\begin{matrix}{{D_{diff}{Cit}} = {( {{Qb} + {Qpre}} )\frac{^{{KoA}\frac{{Qd} - {({{Qb} + {Qpre}})}}{{Qd} \cdot {({{Qb} + {Qpre}})}}} - 1}{^{{KoA}\frac{{Qd} - {({{Qb} + {Qpre}})}}{{Qd} \cdot {({{Qb} + {Qpre}})}}} - \frac{( {{Qb} + {Qpre}} )}{Qd}}}} & (10.2)\end{matrix}$

Finally, the obtained D_(diff)Cit can be inserted into Equation (7) or(8) with the Q_(pre) or Q_(post) and Q_(uf) values as appropriate, andthe equations can be solved to derive the total D_(Cit)*. Here the Ssieving coefficient will now be specific for citrate, S_(Cit). Theobtained total D_(Cit)* is used to derive E=D_(Cit)*/QB_(Cit). Theobtained E allows the calculation of the safety parameter, Csys asdescribed herein regarding safe prescriptions for RCA.

In summary, in the novel arterial circuit limb blood-bolus methodaccording to the present invention, conductivity dialysance may bemeasured by inducing a precise, calculated change in the input plasmaconductivity entering the hemofilter and measuring the response in thefilter effluent fluid. Conductivity dialysance may then be convertedinto citrate dialysance as shown in the above equations. The feasibilityof such conversion depends on the in vivo ratio of the diffusivitycoefficients for conductivity and citrate. This ratio is estimated to beabout 3, and in the range of 2 to 4. The citrate dialysance, in turn,defines the maximum possible systemic citrate level with a giventreatment prescription, which is the safety parameter that is desired tobe maintained and monitored. In a variation of the technique, in theevent that it is not desirable to increase the input soluteconcentration, conductivity dialysance can be measured by introducing acalculated decrease in the input solute concentration and measuring thechange in conductivity of the filter effluent fluid. All of theequations remain unchanged because both (C_(eff)B−C_(eff)1) and(C_(pin)B−C_(pin)1) in Equation (3) will be negative when the inputconcentration is decreased (and QB is appropriately increased) (FIG. 20b).

Any method that induces a known change to the dialyzer input bloodcomposition, which results in a measurable change in the composition ofthe effluent fluid of the hemofilter can be used to measure thedialysance of the hemofilter and then calculate citrate dialysance andis fully contemplated in accordance with the present invention. Thepresent invention also contemplates methods that induce a change in theinput blood composition and measure the effects on the filter outputblood composition.

The effect of access recirculation on the online conductivity dialysancemay also be measured by the method according to the present invention.Below, the differential impact of access recirculation on the onlineconductivity dialysance based filter clearance measurements is reviewedwhen performed with the traditional, fresh dialysis fluid conductivitybolus method versus the circuit arterial limb blood-bolus method of thepresent invention (see FIG. 21). The following will be presumed:

1) The dialysis fluid bolus method, when possible to execute with thehigh/low step functions as described in Kidney International, Vol. 66,Supplement 89 (2004), pp. S3-S24, will be considered equivalent to theeffective dialysance of the circuit that includes the effects of thepossibly present access as well as cardiopulmonary recirculation(D_(eff2)) and systemic conductivity recirculation will be assumednegligible.2) The access recirculation will be measured with a hematocrit sensor(hemodilution) or thermal sensor (thermodilution) based method prior toany online clearance measurement.3) When venous catheter access is used, only access recirculation may bepresent (D_(eff1)). Both methods will allow the calculation of the truefilter dialysance, D_(Filter) before it is altered by any recirculation.4) When a permanent access is used, at least with circuit blood flows upto 300 ml/min, our blood bolus based method will measure D_(Bolus).Assuming that significant systemic and cardiopulmonary recirculation isnot present with our method (this is reasonable with single passconductivity extraction >=80% with Q_(B)<=300 ml/min) and measuringaccess recirculation will allow the derivation of the true filterdialysance, D_(eff) as well as the effective dialysance altered byaccess recirculation only, D_(eff1). This is the data needed for citratekinetics calculations.5) In a permanent access, the dialysate bolus method will measureD_(eff2). Even if the access recirculation R and the permanent accessblood flow Q_(AC) is measured (for instance with the use of the reverseblood line connector device and the hemodilution or thermodilutiontechnique) in the absence of the cardiac output CO, D_(Filter) cannot becalculated.

The terms used in the equations are defined below, wherein thecalculations are depicted in FIG. 21:

Q_(B): effective circuit arterial whole blood water flow forconductivity (Q_(BCond)), adjusted arterial blood plasma water flow forcitrate, (Q_(Bcit))Q_(AC): effective access whole blood water flow for conductivity(Q_(ACCond)), adjusted arterial blood plasma water flow for citrate,(Q_(ACcit))C_(AC): “conductivity solute” concentration in the plasma water in theaccessC_(ArtR): “conductivity solute” concentration in the plasma waterentering the filter (pre-dilution removed), as modified by recirculationC_(ArtRS): “conductivity solute” concentration from the access arterialblood in the plasma water entering the filter (pre-dilution removed), asmodified by recirculationC_(ArtRB): “conductivity solute” concentration from the arterial limbbolus infusion in the plasma water entering the filter (pre-dilutionremoved), as modified by recirculationC_(Ven): “conductivity solute” concentration in the plasma water exitingthe filterC_(B): “conductivity solute” concentration step-up in the plasmaentering the filter over plasma entering the arterial limb of the bloodcircuit during the citrate bolusC_(Cit): “conductivity solute” concentration in the citrateanticoagulantQ_(Cit(B)): flow rate of the citrate anticoagulant during the temporarysodium citrate bolusQ_(pre): pre-filter substitution fluid flow rateQ_(uf): net ultrafiltrationQ_(R): the recirculating circuit venous limb bloodR: the recirculation ratio defined as R=Q_(R)/Q_(B)D_(Filter): true filter “conductivity solute” dialysanceD_(Eff2): effective “conductivity solute” dialysance determined affectedby access and cardiopulmonary recirculation and determined by thedialysate bolus based measurementD_(Bolus): measured “conductivity” dialysance affected by access but notcardiopulmonary recirculation and determined by the blood bolus basedmeasurementD_(Eff1): effective “conductivity” dialysance determined from D_(Bolus)by correcting for access recirculation only

FIG. 21 is a comparison of the effects of permanent access (depicted;however, the calculations are also fully applicable to catheter access)recirculation on the fresh dialysis fluid conductivity bolus basedonline dialysance measurement (D_(effective)) versus the circuitarterial limb blood conductivity bolus based online dialysancemeasurement (D_(Bolus)). D_(Filter) is the intrinsic filter dialysancewith the effects or access recirculation removed. Cardiopulmonary andsystemic recirculation is ignored. R is equal to Q_(R)/Q_(B) and can bemeasured online by hemodilution or thermodilution methods.

$\begin{matrix}{{D\; {Effective}} = \frac{D\; {{Filter} \cdot ( {1 - R} )}}{1 - {R \cdot ( \frac{Q_{B} - {D\; {Filter}}}{Q_{B} - Q_{UF}} )}}} & {{Equation}\mspace{14mu} 1}\end{matrix}$

This describes the relationship between Deff1 and Dfilter with R accessrecirculation. Deff1 is measured by the dialysis fluid bolus method ifthe cardiopulmonary recirculation is negligible or absent as is the casewith venous catheter access. It was derived as follows:

$\begin{matrix}{\mspace{79mu} {{{Deffective}*{CAc}} = {{CArtRS}*{Dfilter}}}} &  1.1 ) \\{\mspace{79mu} {{Cven} = {{CArtRS}*{( {{Qb} - {Dfilter}} )/( {{QB} - {QUF}} )}}}} &  1.2 ) \\{\mspace{79mu} {{CArtRS} = {{R*{Cven}} + {( {1 - R} )*{CAc}}}}} &  1.3 ) \\{{CArtRS} = {{CAc}*{( {1 - R} )/( {1 - {R( {( {{Qb} - {Dfilter}} )/( {{QB} - {QUF}} )} )}} }}} &  1.4 ) \\{\mspace{79mu} {{D\; {Bolus}} = \frac{D\; {Filter}}{1 - {R \cdot ( \frac{Q_{B} - {D\; {Filter}}}{Q_{B} - Q_{UF}} )}}}} & {{Equation}\mspace{14mu} 2}\end{matrix}$

This describes the relationship between Dbolus and Dfilter with R accessrecirculation. Dbolus is measured by the circuit arterial limb bolusmethod if the cardiopulmonary recirculation is negligible or absent asis the case with venous catheter access and in general with this methodwhen the QB is <=300 and QD is 150-200% of QB with a large surface area,high flux filter. R is measured online with the hemodilution orthermodilution technique. This Equation 2 is novel according to thepresent invention and is derived as follows:

Dbolus*CB=CArtRB*Dfilter  2.1)

Cven=CArt*(Qb−Dfilter)/(QB−QUF)  2.2)

CArtRB=R*Cven+(1−R)*CAc+CB  2.3)

CAc=0 (reasonable when single pass bolus extraction is >=80% or if weexamine the recirculation effects on the bolus in isolation)  2.4)

CArtRB=CB/(1−R((Qb−Dfilter)/(QB−QUF))  2.5)

Combining Equations 2.1 and 2.5 and rearranging yields Equation 2.

$\begin{matrix}{{D\; {filter}} = {D\; {{bolus} \cdot \frac{( {1 - R} ) - \frac{Q_{UF}}{Q_{B}}}{1 - {R \cdot ( \frac{D\; {bolus}}{Q_{B}} )} - \frac{Q_{UF}}{Q_{B}}}}}} & {{Equation}\mspace{14mu} 3}\end{matrix}$

This equation is derived from Equation 2 by simple rearrangement andsolution for Dfilter. The Dfilter conductivity dialysance can beseparated into diffusive and convective component, the diffusivecomponent converted into citrate diffusive dialysance and finallysummary citrate dialysance calculated as described earlier.Subsequently, Dbolus citrate and Deff1 citrate can be calculated usingeffective QB as plasma water flow for citrate.

Deffective=Dbolus·(1−R)  Equation 4:

This equation follows from Equations 1 and 2. As discussed above, Dbolusis measured by the novel blood bolus method according to the presentinvention. Deffective (D_(eff1)) can then be calculated using themeasured R value. If a venous catheter access is used, Deff1 will beequal to the effective urea clearance. D_(eff1) must be converted intoD_(eff2), the effective urea clearance including a correction forcardiac output when a permanent (arterial) access is used:

D _(eff2)=(1/(1+D _(eff1)/(CO−Q _(AC))))*D _(eff1)  Equation 5:

As mentioned, in a permanent access, the dialysate bolus method willmeasure D_(eff2). The blood bolus method according to the presentinvention will measure D_(Bolus) and will allow the calculation ofD_(eff1) if the access recirculation R is measured. Finally, if thepermanent access blood flow Q_(AC) is measured (for instance with theuse of the reverse blood line connector device and the hemodilution orthermodilution technique), Equation 5 allows the calculation of thecardiac output CO with some simple rearrangements.

CO=((D _(eff1) *D _(eff2))/(D _(eff1) −D _(eff2)))+Q _(AC)  Equation 6:

The method according to the present invention may allow the measurementof the cardiac output with clinically useful accuracy. The presentinvention contemplates use of this method with a dialysis machine withthe appropriate sensor equipment, access connection reversal device andthe cannulation of a permanent access to measure the cardiac output of apatient during treatment.

The online sensor system (OSS) according to the present invention willnow be further described.

In recent years there has been expansive growth in the field of sensortechnology. There are a multitude of new sensors that measure varioussubstances including glucose, electrolytes, and macromolecules. Most ofthese sensors can be produced to scale to work with very small fluidsamples. The greatest hurdle for these sensors in transitioning to humanclinical use is the safety and regulatory concerns any device that comesinto direct contact with human blood or tissue fluids must alleviate.The present invention provides an online sensor system (OSS) which isdesigned to overcome this problem as a sampling device that generatesplasma ultrafiltrate for analysis by downstream sensor arrays, therebyallowing the indirect measurement of any filterable substance in theblood circulation.

The sensors placed into the OSS do not come in direct contact with humanblood; instead they analyze a fluid sample obtained by ultrafiltrationof circulating blood. An illustration of a basic hemofiltration circuitfor OSS 400 which may be used to extract a small amount of ultrafiltratefor chemical analysis is shown in FIG. 22. Blood is drawn into thecircuit from the patient's access catheter 20, 120, 200 by the bloodpump 22, 122, 222. An infusion pump 34, 134, 234 may add a small amountof infusion solution (e.g., anticoagulant) to the blood to prevent thecircuit from clotting, wherein the blood then passes through thehemofilter 16, 116, 216 and returns to the patient. A small amount offluid, ultrafiltrate, may be extracted from the blood passing throughthe hemofilter 16, 116, 216 by the ultrafiltration pump 26, 126, 226.Hemofilter 16, 116, 216 may be a miniature hemofilter or a simple twocompartment hemofilter. The chemical composition of the ultrafiltratecan then be analyzed for a single analyte or multiple different analytesusing a sensor array 56, 156, 256. The concentration of the analyte inthe blood can then be determined since the dilution of the blood isknown (this will be usually less then 10%) and the sieving of the solutethrough the hemofilter 16, 116, 216 is known. The OSS 400 can beimplemented with any existing device that extracts ultrafiltrate frombody fluids. Specific application of a CRRT circuit as an OSS to measurepatient plasma levels of citrate, calcium, magnesium, glucose, inulinand para-aminohippuric acid (PAH) is provided according to the presentinvention. For patients not receiving CRRT, a small (e.g., 2×3inch-size) OSS system is described herein that can be attached to aperipheral intravenous catheter and can store sufficient anticoagulantand ultrafiltrate to provide 1-2 ml of ultrafiltrate hourly during a24-hour period of intermittent, hourly operation. Such sample size ismore than adequate for the novel sensor technologies.

One advantage of OSS 400 according to the present invention is that itis very safe because the ultrafiltrate is discarded after themeasurements and therefore possible contaminants or allergens in thesensor array 56, 156, 256 part of the circuit cannot come into contactwith the patient. Devices for detecting an analyte in blood have beendeveloped, however those devices bring the sensors into direct contactwith blood in vivo by coupling the device with a venous flow device,such as an extracorporeal membrane oxygenator or hemodialysis machine. Asensor in contact with human blood will require sterilization andadherence to safety procedures to minimize risks to patients. Contactwith human blood will result in biofouling of the sensor, which willpossibly reduce sensor performance. Coatings added to sensor surfaces tolimit degradation and improve performance have the added risk ofpossible adverse patient reactions. It will be mandatory for bloodcontact sensors to go through FDA testing to ensure that they do notcause anaphylaxis in patients. Since the OSS 400 according to thepresent invention uses an ultrafiltrate of the blood, large moleculessuch as proteins remain in the blood and are not available to foulsensor surfaces and thereby reduce performance. The OSS 400 eliminatesthe need for anaphylaxis testing because once the ultrafiltrate passesthe sensor 56, 156, 256 it may be completely discarded. The use of OSS400 can markedly accelerate the time from development of a specificsensor to transitioning to human clinical use either in the testing anddevelopment phase or for routine patient care.

OSS 400 according to the present invention may have differentimplementations. In one embodiment, the OSS 400 may be provided as acompact device (e.g., 2×3 inch-size) for ease of use and immediateapplicability for hospitalized patients (and possibly even foroutpatients for 24-48 hours; as a “chemical Holter monitor”). This formof the OSS 400 only requires a small peripheral IV for access to thepatient's venous blood and is designed to serve as a safeplasma-sampling device. In another embodiment, the OSS 400 may beprovided as a full size CRRT machine OSS. The effluent fluid line 24,124, 224 in such a circuit may be used to provide samples for the sensorarray 56, 156, 256 of the OSS 400. Importantly, in this implementation,more complex assessment of the patient's condition beyond simple plasmaconcentration measurements is possible, including measuring renal andliver clearances of various substances and thereby monitoring renal andliver function online, in real time.

The implementation of the OSS 400 as a small ultrafiltration circuitattached to a peripheral (venous) IV line may be used for patients notreceiving CRRT therapy. This embodiment of the OSS 400 includes a smallhemofiltration device that may extract only a few milliliters ofultrafiltrate per hour from a miniature extracorporeal circuit. A basichemofiltration circuit which may be used to extract a small amount ofultrafiltrate for chemical analysis is shown in FIG. 22. Catheter 20,120, 220 may comprise a small, double lumen intravenous catheter whichmay be placed in a suitable vein. Blood may be removed from the patientusing the arterial pump 22, 122, 222 at a few milliliters per minute. Atthe same time, the infusion pump 34, 134, 234 may add anticoagulationsolution to the blood at an appropriate rate to prevent clotting.Anticoagulated blood from the arterial limb 14, 114, 214 of the circuitmay be pumped through a miniature hemofilter 16, 116, 216 andultrafiltrate may be extracted from the blood by the ultrafiltrationpump 26, 126, 226. Sensors 56, 156, 256 in the ultrafiltration circuitmay analyze the ultrafiltrate for the selected analytes.

FIG. 23 shows a more complete hemofiltration circuit according to thepresent invention which may be used to extract a small amount ofultrafiltrate for chemical analysis. Arterial and venous pressuresensors 402, air-in-fluid detectors 404, a blood in circuit detector 406and line clamps 408 may be added to provide patient safety. FIG. 24shows a hemofiltration circuit which may be used for priming and initialpressure testing of pumps and pressure transducers. All three pumps mayhave very precise flow rates which allows for accurate calculation ofblood analyte concentrations.

The OSS 400 according to the present invention can operate is acontinuous mode or in an intermittent mode in which samples arecollected at pre-selected intervals. In intermittent mode, the entirecircuit can be refilled with the anticoagulant solution. If the infusionpump 34, 134, 234 is run at a slightly higher rate than the arterialpump 22, 122, 222, the entire extracorporeal circuit 12, 112, 212 willbe filled with anticoagulation solution. Running the infusion pump 34,134, 234 for a short period of time after the blood pump 22, 122, 222 isstopped and the blood line is clamped will direct fluid into the accesscatheter, filling it with anticoagulation solution. Only a minusculevolume of infusion fluid is needed for anticoagulation of the circuit,which avoids the risk of infusing an excess amount of anticoagulant intothe patient. When acid citrate anticoagulant is used, the approximately5.4 pH of the anticoagulant-filled circuit will also prevent bacterialgrowth in the event of a contamination.

During continuous operation, the section of the circuit between point Aand point B in FIG. 25 is not exposed to the infusion solutioncontaining an anticoagulant. To address this situation, a triple lumenvenous catheter with an infusion port at the tip of the withdrawal lumenmay be utilized, such as catheter 300 depicted in FIG. 9). This triplelumen catheter 300 allows an anticoagulant solution to be infusedthrough a hole in the lumen wall directly into the entrance of thearterial blood withdrawal path. Since the venous return path containsanticoagulant, the entire triple lumen catheter 300 is continuouslyexposed to anticoagulant. FIG. 26 shows triple lumen catheter 300 in theOSS hemofiltration circuit according to the present invention.

For a case where a sensor requires complete isolation of theultrafiltrate because the testing procedure requires reagents that arevery hazardous to the patient, one of the backflow prevention devices410, 412, 414 in FIG. 27 can be used such that the ultrafiltrateextracted from the blood the fluid can be isolated from the patientcircuit. In one implementation (FIG. 27 a), an air gap device 410 may beused where the input fluid enters a chamber 416 from the top and fallsthrough an air space. If for any reason the sensor system 56, 156, 256causes a backflow to occur, the ultrafiltrate will flow harmlessly outof an opening 418 to the air. This solution may be applicable when theOSS 400 is used in a fixed orientation to gravity, for instance as partof a large CRRT circuit. For the compact size OSS which may be attachedto the patient's body and not have a fixed orientation to gravity, oneof the two valve-system-based backflow prevention devices can be used(FIGS. 27 b-27 c). In FIG. 27 b, a device 412 including a series of twoor more one way valves 420 can be used, such that if the first valvefails, the second valve must also fail before backflow can occur.

In FIG. 27 c, a reduced pressure zone device 414 is illustrated, whereinthe input pressure must exceed a set pressure P to open valve 422, andfluid in a reduced pressure zone 424 is approximately P-0.19P because apressure of P-0.2P is required to open valve 426. Any initial backflowis stopped by valve 426. If valve 426 fails, backflow is prevented byvalve 422 and any increase in pressure above P-0.15P opens valve 428 andthe backflow is diverted out of the device 414. The use of one of thesedevices 410, 412, 414 ensures that if for any reason the OSS 400 causesa backflow to occur, the ultrafiltrate will flow harmlessly out throughthe backflow opening where it is collected and sent to the drain. FIGS.28 a and 28 b show possible locations for backflow prevention devices414 and 410, respectively.

The compact size OSS 400 according to the present invention may beeasily conducted to a peripheral vein of the patient and can betransported with the patient if needed. It is very safe to use becausesensors 56, 156, 256 do not come in direct contact with human blood andafter analyte measurements are made the ultrafiltrate is sent to thedrain. The data obtained may be stored for later retrieval and or may betransmitted by a wireless connection.

The OSS 400 according to the present invention may also be implementedas part of an extracorporeal blood circuit 12, 112, 212 used to provideCRRT in the ICU. The OSS 400 can be implemented with any existing devicethat extracts an ultrafiltrate from body fluids. Specific application ofa CRRT circuit as an OSS to measure patient plasma levels of glucose,citrate, calcium, magnesium, inulin and para-aminohippuric acid (PAH) isdescribed herein. Importantly, when the OSS 400 is implemented as partof a CRRT circuit, truly online, continuous measurement of the plasmaconcentration of any filterable solute for which a specific sensor isavailable becomes possible. Thus, kinetic analysis of the soluteconcentration curve as a function of time becomes clinically feasiblewithout the need for onerous frequent blood sampling. The kinetic dataprovides a wealth of new information, ensures monitoring of the livermetabolic function, and may possibly allow measuring the glomerularfiltration rate and renal plasma flow in real time. Such methods are notcurrently available and are needed clinically.

This implementation of the OSS 400 according to the present invention inan RRT circuit is clinically immediately available, by minormodification of existing RRT devices and by placing the sensor array 56,156, 256 into the effluent line of an RRT device. The OSS 400 may bebest implemented integrated into the RCA systems according to thepresent invention and described herein which were either designed solelyor have the option to deliver purely convection-based, high dose RRTwith fully effective RCA. FIGS. 29 a-29 c show the OSS 400 integratedinto the RCA system according to the present invention running in eitherisolated pre-dilution or simultaneous pre- and post-dilutionhemofiltration mode (only the pre-dilution flow relevant to the OSSapplication is shown). The sensor 56, 156, 256 is placed into theeffluent fluid line carrying ultrafiltrate (and or dialysate) away fromthe hemofilter.

In particular, FIG. 29 a illustrates a configuration for deriving thepatient systemic solute level (C_(sys)) by measuring the ultrafiltratesolute concentration C_(UF) and dividing by the hemofilter sievingcoefficient S for the specific solute. All other parameters are knownvalues and the C_(sys) is calculated according to the formulas shown.Access recirculation is not present. FIG. 29 b illustrates aconfiguration for deriving the patient's systemic citrate level C_(sys)by measuring the ultrafiltrate citrate concentration C_(UF). C_(sys) canbe calculated knowing the arterial plasma flow Q_(PArt) rate, citrateinfusion flow Q_(Fluid1) rate, citrate concentration of the infusionsolution C_(Fluid1) and the filter sieving coefficient for citrate S.The hematocrit sensors 50, 150, 250 and 52, 152, 252 allow thecalculation of the plasma citrate concentration by contributing to themeasurement of the delivered arterial plasma flow and by measuringaccess recirculation (assumed not present here). FIG. 29 c Illustrates aconfiguration for deriving the patient's systemic citrate level C_(sys)by measuring the ultrafiltrate citrate concentration C_(UF) when theincrease in citrate concentration from the anticoagulant infusion in thearterial limb plasma with the pre-dilution effect removed is C_(Jf),access recirculation is R=Q_(PR)/Q_(P) and filter citrate dialysancewith recirculation effects removed is D_(F), plasma citrate bolusdialysance with recirculation is D_(B) and filter systemic citrateeffective clearance with recirculation is D_(E) where D_(E)=D_(B)*(1−R).All variables are known or can be measured and or calculated as shownbefore. The calculations can be applied for any solute for which theabove parameters are known, measured and or calculated.

The effluent fluid contains a wealth of information on the patient'splasma solute composition, but in current clinical practice it isdiscarded without any further analysis. This fluid is a clearcrystalloid with a small amount of albumin, small peptides, andcytokines also present. The transparency and minimal viscosity of theeffluent fluid provide for an ideal environment for an optical- and/orchemical sensor array. The OSS 400 according to the present inventionmay operate in a manner such that solute concentrations are converted tolight (optical) signals by solute-specific, possibly disposable,chemical-optical transducer systems (chips or optrodes) that are exposedto the effluent flow, such as in a possibly disposable, lighttransparent flow-through chamber. Readout of the optical signals may bedone through the light-transparent wall of the chamber or through theoptical filament part of the optrode by a fixed, excitation lightgenerating (if needed) and optical signal capturing and analyzingmodule. Multiple light wavelengths may be used simultaneously for bothexcitation and readout on an unlimited number of sufficiently smallemitting, capturing and analyzing modules.

In a modification of this method, Raman scatter spectroscopy may be usedon the effluent line and the specific solutes may be identified by theirunique Raman spectra. Quantification may be possible by measuring thesignal intensity of specific spectral peaks. The advantage of thismethod is that solute specific chemical-optical probes are not needed asspecificity is provided by the unique Raman spectra of the targetsolute. Citrate will be in a large molar excess compared to most othermolecules in the effluent and it may be possible to quantitate it withRaman scatter spectroscopy, possibly even differentiating free citrate,Ca-citrate and Mg-citrate. The present invention contemplates the use ofRaman scatter spectroscopy to monitor systemic solute levels throughmonitoring the RRT circuit effluent fluid, with the specific example ofmeasuring all species of citrate in the effluent.

Finally, the fluid here is waste fluid and will not be exposed to thepatient's blood again, eliminating any chance of any elements of thesensor getting into direct or indirect contact with the patient. This iscompletely ascertained when a back-flow prevention safety device 410,412, 414 (as shown in FIG. 27) is added before the effluent is exposedto the sensors 56, 156, 256. Finally, the effluent tubing 24, 124, 224can easily be modified to allow the connection of the OSS 400 in thissegment of the CRRT circuit.

The calculation of systemic solute levels from solute levels measured inthe ultrafiltrate including corrections for the effects of accessrecirculation when present is described below. Once real-timemeasurement of a solute is provided in the effluent, a special softwarecalculator may be used to determine the contribution of solute enteringthe extracorporeal circuit from the systemic circulation of the patient(the systemic plasma solute level) and the contribution of solutefreshly infused into the CRRT circuit pre-filter (if the solute iscontained in the pre-filter infusion(s), as may be the case for glucose,citrate, inulin and PAH). This calculation requires that theextracorporeal circuit plasma flow to summary pre-filter fluid infusionratio remain constant for the time of the calculation and is veryreliable when only convective clearance is used, as in the RCA systemsaccording to the present invention.

In the RCA system, plasma flow may be monitored in real time by theonline hematocrit sensors and possibly by a Doppler-based system as wellas shown in FIGS. 29 a-29 b. The pre-filter fluid infusion rate is alsoknown in real-time, as the pre-filter fluid pump 34, 134, 234 of themachine delivers it and it also may be monitored by the function of theDoppler and hematocrit sensors 50, 150, 250 and 52, 152, 252. Therefore,the contribution of solute freshly infused into the circuit blood plasmacan be calculated in real time. The calculation also relies on thesieving coefficient of the solute being known. Such information has beenpublished for glucose and citrate in the literature and can easily bemeasured for most small solutes including inulin and PAH. The sievingcharacteristics of a given solute on the specific filter used are notlikely to change as long as effective anticoagulation is used, and canalso be monitored by the OCM for conductivity or citrate. Thus, in theRCA system, under steady operational parameters, the soluteconcentration measured by the OSS in the ultrafiltrate can beimmediately used to provide the solute level present in the patient'ssystemic blood. The exact calculations for any filterable solute areshown in FIG. 29 a and for the specific example of citrate in FIG. 29 b.The calculations can be provided for CVVHD, CVVHDF and c-SLED as well,as long as measurements are done for the given filter type at fixeddialysate, ultrafiltrate and blood flow and pre-filter fluid infusionrate assuming that the solute transfer properties of such RRT circuitsare defined and monitored by a precise online clearance monitor.However, purely convective clearance may be preferred in this method forgreater reliability of solute transport.

The OSS 400 can be integrated with the RRT device to send an alarm tothe operator when a critical (high or low) threshold of systemic plasmasolute concentration is breached and possibly to automatically adjusttreatment settings to correct the solute level abnormality. A clinicalassessment of the patient with full laboratory parameters may alsofollow. Finally, falsely abnormal solute levels in the blood enteringthe extracorporeal circuit due to recirculation at the catheter tip canbe detected by the recirculation detection feature of the onlinehematocrit sensors 50, 150, 250 and 52, 152, 252 which may be integratedinto the RCA system, and corrections in the calculations are possible,eliminating false solute level alarms with or without an intervention onthe recirculating access as indicated (FIG. 29 c and as explainedbelow).

The terms used in the equations are defined below, and the physicallayout of the OSS 400 with the key calculations is shown in FIGS. 29a-29 b and for recirculation in FIG. 29 c:

Q_(AC): effective access blood water flow specific for the solutemeasuredQ_(B): effective circuit arterial blood water flow specific for thesolute measured; arterial blood plasma water flow for citrate,(Q_(PArt))C_(Sys) (same as C_(AC)): solute concentration in the effective bloodwater in the arterial limit of the accessC_(ArtR): solute concentration in the plasma water entering the filter(pre-dilution removed), as modified by recirculationC_(ArtRSys): solute concentration portion from the access arterial bloodin the plasma water entering the filter (pre-dilution removed), asmodified by recirculationC_(ArtR): solute concentration portion from the arterial limb solute(citrate) infusion in the plasma water entering the filter (pre-dilutionremoved), as modified by recirculationC_(InputR): The solute concentration in the plasma water entering thefilter; this is C_(ArtR) adjusted for pre-dilutionC_(UF): The solute concentration in the ultrafiltrate exiting the filterC_(Inf): solute concentration step-up in the effective blood water ofthe blood entering the filter over the blood entering the arterial limbof the blood circuit during citrate infusion, with pre-dilution removedC_(Fluid): summary solute concentration in the pre-filter fluidsQ_(Fluid): summary flow rate of the pre-filter fluidsQ_(R): the recirculating circuit venous limb blood effective water flow(solute specific)R: the recirculation ratio defined as R=Q_(R)/Q_(B); (measured byhemodilution or thermodilution)D_(Fi1ter): true filter solute dialysance (calculated)D_(Bolus): measured solute dialysance affected by access but notcardiopulmonary recirculation and determined by the blood bolus basedmeasurement for conductivity (OCM) or citrate (citrate sensor)D_(Eff1): effective solute dialysance determined from D_(Bolus) bycorrecting for access recirculation onlyS: summary solute sieving coefficient (S_(Cond), S_(Cit), S_(Solute))These calculations assume:1) All the equations presented and or used in the section on accessrecirculation effects on conductivity dialysance based online clearancemeasurements are referenced here as needed2) Access recirculation, R, is measured online.3) While the general term D, (dialysance) is used, all clearance isconvective for greater predictability of small to medium size solutemovement. However, this method limitation is not mandatory.4) D_(Bolus)* is measured for conductivity and or citrate andD_(Filter)* is calculated.5) D_(Filter)*/Q_(B)>=0.8 and Q_(B) is <=300 ml/min so thatcardiopulmonary and systemic recirculation can be neglected.6) The sieving coefficient is known for both the solute used to measureD_(Bolus)* as well as the solute for which the systemic concentrationneeds to be determined.7) D_(Filter)* is converted to D_(Filter) using the sieving coefficientof the “solute” used for measuring D_(Bolus)* and the sievingcoefficient of the target solute to be measured as well as knowing theeffective blood water flows for both solutes. (These calculations arediscussed with reference to the OCM where in a specific exampleD_(conductivity) is converted into D_(Citrate)).8) The target solute D_(Filter) and R is used to calculate the targetsolute D_(Bolus) and D_(effective1).Specific equations used in the calculations are as follows:

$\begin{matrix}{C_{InputR} = {{\frac{C_{UF}}{S}S} = {{sieving}\mspace{14mu} {coefficient}}}} & {{Equation}\mspace{14mu} 1}\end{matrix}$

The C_(UF) is measured by the OSS and S is known for the target solute.

Equation 2:

$C_{ArtR} = {C_{InputR}\frac{Q_{PArt} + Q_{{Fluid}\; 1}}{Q_{PArt}}}$

C_(ArtR) is derived by adjusting C_(InputR) for the effects of thepre-dilution with Q_(Fluid).Equation 3 (by definition):

$C_{Inf}\frac{C_{Fluid} + Q_{Fluid}}{Q_{PArt}}$

The recirculating solute fluxes originating from the systemiccirculation (C_(Sys)) and from the blood bolus infusion can beconceptually separated (if the post-dilution fluid and or the dialysisfluid target solute concentration is zero as it is for citrate, calciumand magnesium) andEquation 4 follows by definition:

D _(Bolus) *C _(Inf) +D _(eff1) *C _(Sys) =C _(ArtRSys) *D _(filter) +C_(ArtRInf) *D _(filter) =C _(ArtR) *D _(Filter)

In Equation 4, C_(ArtR) is derived from measuring C_(UF), and D_(Bolus),D_(eff1), D_(filter) is either directly measured or calculated. UsingD_(eff1)=D_(Bolus)*(1−R) and solving Equation 4 for C_(sys) (equivalentto C_(AC) or “arterial” access solute concentration) yields

$\begin{matrix}{C_{Sys} = \frac{{C_{ArtR}*D_{F}} - \frac{D_{B}( {C_{Fluid}Q_{Fluid}} )}{Q_{PArt}}}{D_{B}( {1 - R} )}} & {{Equation}\mspace{14mu} 5}\end{matrix}$

In one implementation, the physical design of the access device used forthe OSS 400 and the low Q_(B)/Q_(AC) ratio is expected to eliminateaccess recirculation. However, the above novel calculations are providedwhen the OSS 400 is implemented as part of a (convective) RRT circuitwhere recirculation, although rare, may occur and its elimination maynot be clinically immediately possible. Specific examples for theclinical use of OSS 400 integrated into a CRRT circuit for the simplemeasurement of systemic blood glucose and citrate levels are providedbelow.

For systemic blood glucose monitoring, patients with ARF in the ICUoften have diabetes and/or various degrees of liver dysfunction. In suchpatients, tight glycemic protocols for blood sugar control are oftendifficult to administer safely and can have a high rate of hypoglycemiccomplications. Since these patients will often have baseline mentalstatus changes as well and may be sedated and their liver's ability torespond to hypoglycemia may be compromised, a real risk of catastrophichypoglycemic events is apparent. Frequent blood sugar monitoring bystandard clinical methods is costly, labor intensive and may beinconvenient to the patient. Reliable glucose sensors have beendeveloped by several companies in the quest for creating the “artificialendocrine pancreas” and are currently in preclinical or clinical trials.They all have to satisfy FDA safety regulations delineated for devicesthat come into direct contact with human blood or body fluids inside thebody. However, such safety concerns would not apply if the sensors weredeployed in the OSS allowing immediate human clinical trials of theclinical feasibility and value. These sensors could be immediatelyplaced in the effluent line of a CRRT circuit.

For systemic blood citrate (and calcium) level monitoring, RCA duringthe delivery of CRRT (and possibly home nocturnal dialysis in thefuture) is emerging in the literature as the anticoagulation method ofchoice. In all applications of RCA in any form of RRT, there is asignificant amount of citrate infused into the extracorporeal circuit. Aportion of the citrate infused into the circuit ultimately enters thepatient and is converted into bicarbonate by the metabolic action of theliver. When the liver function is markedly compromised, citrate is notconverted, with consequent systemic citrate accumulation andhypocalcemia, hypomagnesemia and metabolic acidosis. In-coordinateprescriptions can also lead to net calcium gain or loss in the circuit,leading to further complications. In current clinical practice,laboratory values including Lytes 7 and total and ionized calcium aremeasured every 6 hours to detect a lack of citrate metabolism andabnormalities of calcium homeostasis. This increases the cost of RCA anddoes not provide complete safety as citrate accumulation can occur in1-2 hours with sudden, marked changes in liver function with the currentRRT prescriptions targeting higher treatment goals and fluid flows thanin the past. Laboratory monitoring is obviously not an option in thehome setting.

The online citrate, calcium and magnesium sensor according to thepresent invention may detect systemic citrate, calcium and magnesiumlevel changes in real time before clinically significant derangementscould occur, completely eliminating concerns about these solutes. Thisis likely to increase physician use of RCA in RRT in the ICU and mayallow deployment of RCA in the home setting with the RCA home systemdescribed herein. The online citrate, calcium and magnesium sensor caneasily provide online clearance measurements. Finally, the dosing of thereplacement calcium plus magnesium infusion in RCA for CVVH is in partdetermined by the systemic citrate level, and the online citrate sensorcan provide this information continuously.

The online citrate sensor is an implementation of the OSS with aspecific optical citrate sensor that is placed into the CRRT circuiteffluent fluid line carrying ultrafiltrate and or dialysate away fromthe hemofilter (FIG. 29 b). Citrate present in the ultrafiltrate and/ordialysate fluid will be in the 0 to 15 mM range under normal operatingconditions. In one example, the citrate sensor may utilize luminescencefrom a complex of citrate with a europium-based ligand (e.g., ChemicalCommunications 2005, pages 3141-3143: Parker et al, “A pH-insensitive,ratiometric chemosensor for citrate using europium luminescence”). Thissensor technology is based on allowing citrate to reversibly associatewith a europium ion-based complex. During spectrophotometry, thecitrate-europium complex is exposed to an excitation light source andluminescence is measured at different wavelengths. The citrateconcentration in the sample is determined by ratiometric analysis,calculating the ratio of the luminescence intensities at the differentwavelengths. This citrate sensor technology has no interference fromphosphates, lactate or bicarbonate, has a response time in themillisecond range and is not affected by pH changes in the range of4.8-8.0. In accordance with the present invention, the abundant, clearcrystalloid CRRT effluent fluid is eminently suitable forspectrophotometry analysis online. As the detection relies onluminescence changes with europium and citrate association anddissociation, there is no consumption of reagents (if the europiumligand is immobilized in the flow-through detection chamber) or fadingas with electrode or enzyme based methods of citrate detection publishedby others in the past. The published optical system was fine-tuned tothe 0-3 mM citrate concentration; however this may be adjustable bychanging the amount and chemical design of the europium complex used.

In accordance with the present invention, the sensor 56, 156, 256 may becreated by either diverting a small amount of the CRRT effluent 600 (<1ml/minute to conserve reagents) for mixing with the europium-ligandcontaining detection reagent 602 in a flow-through light transparentchamber 604 (FIG. 30 a) or by covalently immobilizing the detectoreuropium complex onto the wall of a flow-through light transparentchamber 604 in the fluid pathway of the entire effluent (FIG. 30 b).FIG. 30 a illustrates a citrate, calcium and magnesium sensor 56, 156,256 according to the present invention for use in a continuously flowingfluid circuit. The system mixes the opto-chemical probes 602 and thedrain fluid 600 containing citrate, calcium and magnesium before makingoptical measurements. A light source 606, prism 608, and mirrors 610create a measurement optical path 612 and a control optical path 614.Probe binding results in changes in light absorption and or emission atspecific wavelengths, where changes in light intensity may detected byoptical detectors 616 (e.g., charge coupled devices) and converted intoelectronic signals. The total citrate, calcium and magnesiumconcentrations may be determined by a processing unit using calculationsbased on the obtained data. FIG. 30 b illustrates a citrate, calcium andmagnesium sensor 56, 156, 256 for use in a continuously flowing fluidcircuit which utilizes chemical probes 618 immobilized, such as in ahydrophilic polymer film that coats surfaces, in a light transparentcuvette 604. The probes 618 bind citrate, calcium and magnesium whichfreely diffuse between the drain fluid 600 and the cuvette 604, whereprobe binding results in changes in light intensity that may be used todetermine the total citrate, calcium and magnesium concentrations asabove.

Due to the tight coordination of the europium ion into the complexcovalent bond chemical structure of the ligand (akin to the coordinationof the iron (Fe) ion in the heme group), a sensor 56, 156, 256 based onthe europium ligand-coated chamber 604 should be very stable for days ofcontinuous operation. The flow through chamber 604 may be locked into aspectrophotometer module on the machine that provides excitation light606 (e.g., at 384 nm wavelength) and luminescence detection 616 (e.g.,at 579 nm and 616 nm wavelengths). For patient safety and increasedaccuracy, two citrate sensors may be used. Sensor values may be comparedand, if they deviate by a predefined value, the system will signal analarm to prompt corrective measures. One light transparent chamber 604with two optical paths 612, 614 could be used for the system as shown(FIGS. 30 a and 30 b).

There are multiple other chemical-optical sensing technologies which mayalso be used for citrate (see, for example, Anslyn et al, Tetrahedron,Volume 59, Number 50, 8 Dec. 2003, pp. 10089-10092(4)) and may form thebasis of the optical-chemical transducer part of the online citratesensor according to the present invention. However, it is understoodthat the application of simultaneous monitoring of citrate, calcium andpossibly magnesium levels in effluent fluids of extracorporeal bloodtreatment devices is fully contemplated according to the presentinvention, regardless of the specific sensing technology used. Onephysical implementation includes a combination of possibly disposable,optical-chemical transducers and possibly fixed, non-disposable opticalexcitation, readout and analysis modules, wherein the latter may beseparated from the effluent fluid by a light-transparent, sterile/fluidbarrier (flow through chamber). Once real-time measurement of citrate,calcium and magnesium is provided in the effluent, a software module maydetermine the systemic citrate concentration based on the methodologydescribed herein for any filterable solute in general. Specific use ofthe data obtained are described below.

For detection of systemic citrate accumulation due to lack of livermetabolism, the machine can send an alarm to the operator when acritical threshold of systemic plasma citrate concentration is exceeded.A clinical assessment of the patient and the CRRT treatment with fulllaboratory parameters can then follow with appropriate changes to thecare of the patient. Increasing citrate levels in the blood entering theextracorporeal circuit due to recirculation at the catheter tip can bedetected by the recirculation detection feature of the online hematocritsensor which may be integrated into the RCA system of the presentinvention, thereby eliminating false citrate alarms and allowing forexchange of the dysfunctional access catheter in a timely manner.

The online citrate sensor may be used to guide the calcium plusmagnesium infusion dosing. During the operation of the RCA systemaccording to the present invention (and in other CRRT systems with RCA),the ultrafiltrate calcium content and magnesium concentration is equalto the total patient systemic plasma calcium or magnesium concentrationadjusted for the degree of pre-dilution with the calcium and magnesiumfree pre-filter fluid, respectively. The high clearance goals achievedwith the RCA System ensure that only chloride, albumin, lactate,bicarbonate and citrate can persist as anions in high concentrations inthe patient's plasma. Other anions including phosphate will be quicklyreduced to physiologic levels by the effects of the CVVH procedure, andsystemic pH will also approximate the normal 7.4. The anionbeta-hydroxybutirate can be eliminated by administering glucose andinsulin if needed. Under these conditions, the patient's systemic totaland ionized calcium and magnesium levels can be programmed as long asthe only clinically significant variable, the current systemic plasmacitrate level is known, which may be provided by the online citrate andcalcium sensor according to the present invention. (Lactate, the otherpatient-specific clinically-variable anion does not seem to affectionized Ca levels sufficiently to be of clinical concern). Since thesystemic blood citrate level is derived by the online citrate sensor andthe plasma albumin concentration of the patient is known from laboratorystudies (and is unlikely to fluctuate quickly), a desirable totalsystemic plasma calcium and magnesium concentration can be targeted (aconstant fraction of which, in turn, will appear in the ultrafiltrate asnet loss from the patient) to keep the ionized calcium (and magnesium)in the physiologic range. Using this programming of calcium andmagnesium replacement, all patients may be at target ionized calciumvalues with much lesser need for frequent monitoring of their laboratoryparameters. It is also of importance that the sieving coefficient ofcalcium and magnesium in the RCA system may be near 1.0 (different from0.6 in regular CVVH without citrate) due to the unique RCA fluid designof the present invention and the fact that only convective clearance maybe used.

Next, an online filter clearance (performance) and patency monitor isdescribed. Accuracy of the online citrate and calcium sensor accordingto the present invention can be easily tested by deploying the sensor induplicate and by varying the circuit plasma flow to citrateanticoagulant infusion ratio by changing the blood flow rate andpre-filter fluid flow rate ratio (citrate blood bolus based method).This will result in an immediate and predictable change in theultrafiltrate citrate level. The changes measured by the sensor can becompared with the predicted changes to monitor filter patency and sensoraccuracy. Ideally, the sensor is checked initially at the time of thepriming of the circuit with a modified saline solution that contains Ca,Mg and citrate at the start of the CRRT procedure. Subsequentmeasurements should match the initial filter and sensor performance.Once the citrate clearance is known (particularly in a purely convectionbased RRT treatment as delivered with the RCA systems), the clearance ofany solute with a known sieving coefficient on the specific type ofhemofilter used can be easily calculated. This will be of great value topharmacists with the increasingly widespread use of high clearancetargets in RRT protocols and concomitant very effective removal ofvarious medications. The signal to baseline ratio of the citrate basedonline clearance monitor can be as high as 1:1 (by doubling the citrateinfusion rate temporarily), possibly ensuring more accurate measurementsthan existing technology can provide (depending on the resolving abilityof the citrate and calcium sensors as well). The current gold standardonline clearance method relies on varying the sodium concentration ofthe dialysate and detecting the changes by monitoring the conductivityof the circuit effluent. The data obtained mainly reflects the movementof the small solute sodium and may be of lesser value when the clearanceof middle to large size molecules is investigated. In contrast, when OSStechnology of the present invention for high molecular weight inulin isused (see below), the filter online clearance of middle and largemolecular weight solutes can also be monitored, which cannot beaccomplished by other devices currently in clinical use. Monitoring suchclearance may become important in the future to follow the efficacy ofthe removal of cytokines and antibiotics through the filter with highvolume CVVH.

Finally, it should be noted that in the event of a citrate sensormalfunction, the RCA system according to the present invention willstill continue to operate and provide RCA for RRT in a safe default moderelying on their safe prescription algorithms and OCM modules for themonitoring of filter performance and hence, indirectly, citrateclearance.

The clinical use of the OSS according to the present inventionintegrated into a CRRT circuit to obtain systemic solute concentrationkinetic curves as a function of time to calculate and monitor livermetabolic function, glomerular filtration rate and renal plasma flowwith specific examples for citrate, inulin and PAH monitoring is nowdescribed. Despite significant advances in ICU therapy, the mortality ofacute renal failure (ARF) requiring renal replacement therapy hasremained essentially unchanged in the past decades at very high levels,particularly when ARF is caused by acute tubular necrosis (ATN) in thesetting of the systemic inflammatory syndrome (SIRS) with or withoutmulti-organ dysfunction syndrome (MODS). Emerging data suggests that thevery early (within 0-24 hours of the start of the acute kidney injury(AKI), initiation of high dose convective CRRT may have a favorableimpact on patient survival and recovery of renal function. It isexpected that in the future, high dose CVVH will be started earlier fora broader group of patients as long as difficulties of the procedure areovercome (as described with reference to the RCA system according to thepresent invention).

However, the new treatment approach will create new clinical dilemmas aswell. Many patients will be non-oliguric, and with the high clearancegoals, traditional markers of renal function including blood ureanitrogen (BUN) and creatinine will be in the normal or near normalrange. Furthermore, the levels of these solutes are also influenced by amultitude of factors other then renal function including, but notlimited to, the amount of muscle mass and muscle breakdown forcreatinine, and tissue catabolism, the use of corticosteroids, and thepresence or absence of gastrointestinal bleeding for BUN. Preciseinformation on renal function will be indispensable for propermedication and CRRT dosing and to know when renal recovery has occurredto the degree that the CRRT could be stopped. As a result, thedevelopment of new, clinically feasible methods to assess glomerularfiltration rate and renal function will be necessary.

Similarly, currently there is no reliable, inexpensive clinical methodto follow liver parenchymal function in critically ill patients.Laboratory tools in current use provide only indirect assessment and maytake 12-24 hours to reflect marked changes in liver function. The onlyalternate to routine chemistry testing, the ICG-Pulsion technology anddevice, is fairly costly, does not provide continuous data, and hasfailed to gain wide-spread use to date. More accurate and real-timeassessment of liver function is needed for the safety of RCA thatusually depends on primarily the liver to clear the bulk of the citrateentering the patient's body. Timely information on the metabolicfunction of the liver would also be helpful in the management of acutelyill liver failure patients being evaluated for liver transplantation andin the post-liver transplantation period.

The present invention provides a method of kinetic analysis of systemicconcentration curves obtained by the OSS as a function of time forvarious solutes that loan be used to determine liver metabolic function,glomerular filtration rate, and renal tubular secretory function in realtime, online. The description below reviews the theoretical principle ofsolute kinetic modeling as relevant to the clinical tool according tothe present invention, utilizing the specific example of citrate. Theuse of two additional specific substances are then briefly reviewed thatcould be of immediate interest in clinical practice.

An explanation of the theoretical principle of single pool kineticmodeling of solute (e.g. citrate) loading into the apparent solutevolume of distribution of the patient treated with CRRT and clearance ofthe solute (e.g. citrate) from the patient by the CRRT circuit and bodyclearance mechanisms (metabolism and/or elimination by the liver and/orkidneys) is described below. While citrate is used in this example, theequations are applicable to any water-soluble substance.

Citrate loading (generation) into the patient in CRRT occurs through theinfusion of new anticoagulant into the circuit. The systemic citratekinetics during citrate anticoagulation are shown including citrategeneration, citrate body clearance and citrate filter clearance,including the citrate mass balance fluxes in the patient and theextracorporeal circuit, are shown in FIG. 31. These concepts can begeneralized to any solute that enters the body and/or is produced in thebody at a steady rate and is cleared from the body through aconcentration dependent mechanism by metabolism and/or elimination byfiltration and/or secretion by the liver, kidney and/or the CRRT circuitas applicable. FIG. 32 is an explanation of solute fluxes in theextracorporeal circuit during CRRT using citrate as a small soluteexample, wherein the citrate load in the circuit is the fraction of thenewly infused anticoagulant that is not cleared on the filter in asingle pass (further correction is needed when access recirculation ispresent). When the blood flow, anticoagulant flow, net ultrafiltrationamount, and replacement fluid flows as well as the filter performanceare constant, this amount is also constant. Citrate removal from thepatient is the summary of the citrate cleared from the systemic blood ofthe patient on the hemofilter and the citrate cleared by the patient'sbody, predominantly by metabolism in the liver. These mass fluxes ofcitrate can be described by equations as shown below. The definitions ofthe parameters used in the calculations are as follows:

C_((t)) (mmol/L): the patient's systemic plasma citrate concentration at“t” time point after CVVH startedC₍₀₎ (mmol/L): the plasma citrate concentration at the start of CRRTwith RCA, defined as zeroC_((steady)) (mmol/L): the plasma citrate concentration when the steadystate is reachedT_((90%)): (minutes): the time it takes to build up the plasma citratelevel to 90% of the steady state valueV_((d)) (L): the patient's volume of citrate distribution (predicted tobe equal to the extracellular fluid volume)G (mmol/min): the net citrate load into the patient from the pre-filterfluid after passing through the filterK (L/min): the total clearance of citrate from the patient's body thatis the summary of:K_((b)) (L/min): the body clearance or metabolism of citrate (theequivalent of K_(r) in the urea equation)K_((f)) (L/min): filter clearance of systemic citrateB (L/min): the net change in V per minute (net ultrafiltration rate)Q_(B): effective circuit arterial blood water flow specific for thesolute measured; arterial blood plasma water flow for citrate,(Q_(PArt))C_(Inf): citrate concentration step-up in the effective blood waterentering the filter during baseline anticoagulation over the effectiveblood water citrate concentration entering the arterial limb of theblood circuit with pre-dilution removedC_(Bolus): citrate concentration step-up in the effective blood waterentering the filter during the citrate bolus over the effective bloodwater citrate concentration entering the filter with baselineanticoagulation, with pre-dilution removedQ_(R): the recirculating circuit venous limb blood effective water flow(solute specific)R: the recirculation ratio defined as R=Q_(R)/Q_(B); (measured byhemodilution or thermodilution)D_(Bolus): measured solute dialysance affected by access but notcardiopulmonary recirculation and determined by the blood bolus basedmeasurement for conductivity (OCM) or citrate (citrate sensor)D_(Eff1): effective solute dialysance determined from D_(Bolus) bycorrecting for access recirculation only

R is measured as discussed previously herein. Using the citrate, calciumand magnesium sensor features of the OSS according to the presentinvention as well as the novel citrate blood bolus-based onlineclearance method described herein for conductivity and fully applicablefor citrate (after making the adjustments for the effective QB being QPfor citrate), citrate DBolus is measured and Deffective1 is calculated.The following will be true:

1.G=Cinf*(QBCit−DBolus) 2.K(f)=Deffective1=DBolus*(1−R)

The change in the systemic concentration of citrate as a function oftime will be determined by the difference in the positive citrate fluxinto the patient (G) that is constant and the negative citrate removalflux (filter and body clearance multiplied by the systemic citrateconcentration), which negative flux is variable and is determined by thechanging systemic citrate level. The mathematical formula is shown inequation 1.

d(CV)/dt=G−(K _((b)) +K _((f)) *C(single pool, variable volume citrateequation)  1)

This equation will be clearly familiar to nephrologists. This is, infact, the well-known formula for the single pool kinetic modeling ofurea removal during hemodialysis. The following differences should benoted:

a. G is body generation of urea whereas it is a steady patient load ofcitrate here

b. Urea distributes in total body water whereas citrate distributes onlyin the extracellular volume (ECV)

c. Urea clearance is defined as whole blood volume per minute andcitrate as plasma volume per minute (following from their respectivevolumes of distribution)

d. The relative importance of G and K_((b)) is much greater for citrateduring RCA for RRT than for urea during traditional hemodialysis

However, none of these differences will affect the applicability of theequation or its solution. Single pool modeling can be reliably used asthe rate of solute transfer per hour is fairly low in CRRT and thecitrate volume of distribution is the ECV with rapid equilibration fromthe intravascular space (intracellular levels are kept low mandatorilyby metabolism to prevent interference with intracellular calciumsignaling and probably by the lack of high capacity transmembranecarriers in most tissues except the liver and to a lesser degreeskeletal muscle.) The mathematical solution developed for urea singlepool kinetic modeling will therefore be applicable to predictingsystemic citrate levels at any time point of the RCA for CVVH treatment.The solution of Equation 1 yields Equation 2:

C=C ₍₀₎((V−B*t)/V)exp(((K _((b)) +K _((f)) +B)/B)+(G/(K _((b)) +K _((f))+B)))*(1−((V−B*t)V)exp((K _((b)) +K _((f)) +B)/B)

Fortuitously, the net ultrafiltration per hour (B) in CRRT is relativelynegligible when compared to the ECV of the patient and the equation canbe simplified by eliminating B while preserving clinically adequateaccuracy to give the solution for a single pool, fixed volume citratekinetic model (Equation 3):

C=C ₍₀₎ e−exp((K _((b)) +K _((f)) *t/V)+(G/(K _((b)) +K_((f))))*(1−e−exp((K _((b)) +K _((f)))*t/V)

FIG. 33 illustrates plasma citrate concentration in the patient duringRCA. The systemic plasma citrate concentration kinetic curve predictedby Equation 3 can be obtained by the OSS of the present invention whenimplemented as a citrate sensor in the effluent line of a CRRT circuit.In the clinical setting, all variables that determine the shape of thekinetic curve of the individual patient can be exactly defined by thetreatment operational mode and the CRRT fluid composition(s) as well ascircuit blood and CRRT fluid flow rates and/or measured by the onlineblood bolus dialysance method described herein. The parameters areconstant (C₍₀₎, K_((f)) and G) or near constant (V_((d))) at fixedcircuit plasma and CRRT fluid flow rates. The V_((d)) can be estimatedfairly accurately from anthropometric data. Therefore, for a givenpatient, the K_(b) value can be mathematically derived from the systemiccitrate concentration curve imaged by the online citrate sensoraccording to the present invention. Any subsequent change in the K_((b))will result in predictable changes in the systemic plasma citrateconcentration and will be detected in real time by monitoring thisvariable, C_((t)), by the OSS. Clinically important predictions ofEquation 3 are as described below.

In steady state when the systemic citrate concentration is constant, thecitrate load is equal to citrate removal, Equation 4:

G=C _((steady))*(K _((b)) +K _((f)))  4)

It follows that C_((steady)) is defined only by the CRRT treatmentsettings defining G and K_((f)) and the patient's citrate metabolismK_((b)) and is not influenced by the citrate volume of distribution,Equation 5:

C _((steady)) =G/((K _((b)) +K _((f)))  5)

It is then shown that if a CRRT prescription is provided that achievesmore than 70% single pass clearance of the anticoagulant citrateinfusion on the filter, proportionally keeping G low and K_((f)) high,the C_((steady)) cannot exceed 2 mmol/L even if K_((b)) is zero(consistent with no metabolism of citrate by the patient's liver),regardless of the magnitude of prescribed clearance goals (if C_(Inf) isaround 5-6 mM). Such a prescription is important to the safety of RCA inRRT when the liver function is either unknown or is known to be severelycompromised. Such prescriptions in current clinical practice are limitedto the mainly diffusive treatments of CVVHDF with high dialysate flowrates and c-SLED. Safe prescriptions based on purely convectiveclearance accomplishing high treatment goals are provided for the firsttime by the dosing programs of the RCA system and method according tothe present invention.

When a CRRT prescription is used that allows for dangerous citrateaccumulation if the patient's liver is not metabolizing citrate (suchprescriptions are more fluid and cost efficient and could be used forabout 90% of patients who do not have liver failure), it is important toknow clinically how long an individual patient needs to be monitoredclosely after the initiation of RCA for CRRT to reliably determinewhether he or she can metabolize the infused citrate, particularly ifthe online citrate sensor of the present invention is not used. Assumingthe systemic citrate concentration at the start of the RCA, C₍₀₎ iszero, the time to reach 90% of the predicted C_((steady)) based on theassumed liver function, T_((90%)) can be calculated, as in Equation 6:

T _((90%))=(V _((d))*ln(10))/(K _((b)) +K _((f)))  6)

This equation shows that a patient with liver failure with K_((b)) zero,large ECV (V_((d))) and a CRRT prescription with a low clearance goal(and resultant low G and K_((f))) may take up to 5-10 hours to reachtoxic citrate levels, but nevertheless will reach these levelseventually. Monitoring should cover this period and adequacy of livermetabolism should not be concluded based on relatively low citratelevels in the first few hours of treatment. Using these concepts, allpatients with insufficient liver function at start can be correctlyidentified in the first few hours of RCA with CRRT, particularly whenthe OSS is used to monitor citrate levels and K_((b)) in real time.

An example of imaged systemic citrate plasma concentration curves as afunction of time are provided in FIG. 34 a (normal operation of CRRTwith RCA). FIG. 34 a illustrates citrate concentration measured by acitrate sensor in the drain circuit of an RRT machine utilizing RCA withfixed CRRT prescription settings that result in the development of acitrate steady state determined by the CRRT settings and the patient'scitrate metabolism. FIG. 34 b illustrates citrate concentration measuredby a citrate sensor in the drain circuit of a dialysis machine utilizingRCA. When the patient experiences hepatic failure and no longermetabolizes citrate, the steady state is disrupted and the plasma andultrafiltrate citrate concentration will increase until another markedlyhigher steady-state citrate level is reached. The magnitude of change inthe citrate level will depend on the CRRT settings. In FIG. 34 b, whenafter a period of normal operation of RCA with CRRT the liver functionof the patient changes (deteriorates) suddenly (for instance, apreviously stable patient tolerating RCA for CRRT well may develop liverfailure after a cardiac arrest and resuscitation and subsequent citrateaccumulation in as little as one to two hours if the RCA for CRRT iscontinued). Such a complication would not be detected in time with onlyroutine every-six-hour monitoring of total and ionized calcium levels,as is the current clinical practice. This is where the unique value ofthe online citrate sensor according to the present invention as a safetydevice may be fully realized and demonstrated.

Finally, knowing the value of K_((b)) in real time has other benefits aswell. For example, it also means that citrate conversion intobicarbonate in the patient's body can be calculated exactly, allowingaccurate determinations of bicarbonate mass balance during RCA for CRRT(the greatest precision is provided by the RCA system where all solutemovement is convection based and all fluid flows are provided flexibly,but in tight coordination and are continuously monitored by thehematocrit and Doppler sensors and the volumetric pumps of the system).This allows for exact calculation of net bicarbonate gained or lostthrough the RCA for CRRT procedure with its implications for thepatient's acid-base balance.

The use of the OSS according to the present invention to monitor liverfunction through citrate levels, glomerular filtration rate throughinulin levels and renal tubular secretory function through PAH levels isnow described. For all of these applications, the present inventionprovides a method of keeping the single pass filter extraction of themeasured solute below 50% to increase the sensitivity of the method.

For monitoring liver metabolic function with the OSS, the OSS willobtain a kinetic curve of systemic plasma citrate levels as describedabove and once a steady state is reached, will continuously display theC_((steady)) value of systemic citrate. As shown in Equation 5:

C _((steady)) =G/(K _((b)) +K _((f)))  5)

K_((b)) is the liver clearance of citrate and has been measured to bebetween 0.2-0.5 L/min in ICU patients. The value of K_((f)) will be0.03-0.07 L/min with CRRT clearance goals in the range of 20-35ml/kg/hour as current clinical practice. Since K_((b)) is almost 10-foldgreater than K_((f)), even small percent changes in K_((b)) will besensitively reflected in the C_((steady)) value if the single passcitrate extraction on the filter is 50% or less. This makes the systemicsteady state citrate level an excellent marker of liver perfusion andmetabolic function. Sudden decreases in liver function will be reflectedin the imaged systemic citrate level almost immediately (FIG. 34 b),alerting the health care team to this complication hours beforederangements of blood clotting (INR) or alterations in other liverfunction tests could be expected. The only currently available,distantly similar clinical method to image the liver metabolic function,the ICG-Pulsion device is based on a bolus IV injection and subsequentselective liver clearance of a fluorescent label conjugated ICG moleculewith the transcutaneous imaging of the washout of the fluorescent labelfrom the patient's circulation. This application is costly, it hascaused adverse reactions, and it does not provide continuous 24-hourmonitoring and so far has failed to gain a wide user base.

Monitoring renal function with the OSS with inulin andpara-amino-hippuric acid (PAH) can also be accomplished according to thepresent invention. Traditionally, inulin has been the “gold standardsolute” used to monitor glomerular filtration rate in human renalresearch protocols. Inulin is an inert polysaccharide of varyingmolecular size that is non-toxic, not metabolized by the human body andis eliminated solely by glomerular filtration without any tubularsecretion or reabsorption. According to the present invention, inulinmay be introduced into the CRRT circuit (and the patient) with theanticoagulant infusion pre-filter and the exact same kinetic modelingused as provided for citrate to describe its accumulation andelimination; therefore according to Equation 5:

C _((steady)) =G/(K _((b)) +K _((f)))  5)

The order of magnitude of the targeted C_((steady)) value will bedefined by the sensitivity of the inulin sensor in the effluent line ofthe CRRT circuit and can be achieved by carefully correlating theconcentration of inulin in the anticoagulant infusion with the infusionrate. If a simple, sensitive inulin sensor is not available, inulin canalso be provided conjugated with a non-toxic fluorescent or anotherchemical label for convenient optical detection. One difficulty may bethat the K_((b)) value of interest for inulin (the glomerular filtrationrate of the patient in acute renal failure on CRRT) will fall in therange of 0.000 to 0.050 L/min. Obviously, most patients' GFR will beclose to zero initially with the values increasing when recovery ofrenal function is occurring. At the same time, the K_((f)) will bearound 0.03-0.07 L/min with CRRT clearance goals in the range of 20-35ml/kg/hour as mentioned above. Since the monitored parameter K_((b)) issmaller than K_((f)) (a fixed value with a fixed CRRT prescription), theC_((steady)) inulin will be a less sensitive marker of GFR and recoveryof renal function than citrate levels are of liver function. One way toimprove the sensitivity of the method is by using inulin enriched inlarger inulin polymers (up to molecular weight of 10-60 kiloDaltons)that may have a significant sieving phenomenon on the hemofilter but notin the glomerulus, and correspondingly may have a markedly reducedK_((f)) when compared to standard inulin with mostly smallerpolysaccharide oligomers. As an added benefit, the detection of largemolecular weight inulin can be used as an online clearance-monitoringtool for middle and large molecular weight solutes (for instance topredict the continued effectiveness of convective cytokine removal insepsis). Such monitoring technology does not exist in current clinicalpractice.

While these maneuvers to improve the sensitivity of the inulin-basedmethod to monitor the recovery of renal function may work, thesimultaneous use of para-amino-hippuric acid (PAH) or another, watersoluble and ultrafilterable, non-toxic small solute undergoing extensivetubular secretion in the kidney, may be recommended to increase thesensitivity of monitoring renal function on CRRT. PAH may be introducedinto the CRRT circuit and the patient with the anticoagulant infusionfollowing the same principles as for citrate and inulin. Equation 5 isagain used to describe the relationship of the systemic steady state PAHconcentration with renal PAH clearance:

C _((steady)) =G/K _((b)) +K _((f)))  5)

PAH is a small organic acid solute that is non-toxic, clearedexclusively by the kidneys and has been extensively used in renalresearch protocols. Its K_((f)) will be around 0.03-0.07 L/min with CRRTclearance goals in the range of 20-35 ml/kg/hour, similar to citrate.However, PAH is cleared by the kidneys by both glomerular filtration andby a very active tubular secretory mechanism as well. As a result, PAHclearance under normal conditions is equal to the renal plasma flow andcan be up to 0.6 L/minute, about 10-fold higher then K_((f)). Initially,when the patient has ARF with or without oligo-anuria and is started onCRRT, the PAH clearance may be zero. However, very significant increasescan be expected with incremental recovery of kidney function and tubularsecretory function. Therefore, online monitoring of the PAH C_((steady))level may prove a sensitive and specific method for the early detectionof ongoing recovery of renal (tubular) function. Similar to inulin, theorder of magnitude of the targeted C_((steady)) value will be defined bythe sensitivity of the PAH sensor in the effluent line of the CRRTcircuit and can be achieved by carefully correlating the concentrationof PAH in the anticoagulant infusion with the infusion rate. Alsosimilarly, if a simple, sensitive PAH sensor is not available, PAH canalso be provided conjugated with a non-toxic fluorescent or otherchemical label (with an emission wavelength different from thefluorescent inulin label's, if the two labeled compounds are to be usedsimultaneously) for convenient optical detection.

The OSS according to the present invention may also be implemented as acomprehensive safety module to provide online, truly continuous displayof the systemic plasma total calcium, magnesium and citrate levelsduring any implementation of extracorporeal blood purification usingregional citrate anticoagulation. Several RRT systems have beendescribed herein that can provide RRT with RCA safely. In these systems,appropriately designed fluid compositions and carefully programmed fluidflows ensure a predictable and neutral calcium and magnesium massbalance, and in default operational modes preclude the development ofcitrate accumulation even if the patient has liver failure. However,more replacement fluid efficient (and thereby more economic)prescriptions can be used for about 90% of patients who can metabolizecitrate. The clinical problem is that patients can deteriorate and stopmetabolizing citrate at any time during their treatment course. Onlinecitrate level monitoring is therefore necessary with such prescriptionsand can be implemented as described herein. Stable filter performance isimportant to the safety of diffusion based RRT with RCA prescriptions.The OCM according to the present invention may be used; however, itprovides only indirect information on citrate clearance that may notsuffice for the higher safety prerequisites of home RCA protocols.Finally, calcium and magnesium levels are maintained through themaintenance of mass balance in the RRT circuit. However, even with thebest design, a catastrophic system failure may occur, one example beingthe puncture of the calcium plus magnesium replacement infusion linewith subsequent failure to infuse these ions into the patient as needed.When high blood flows are utilized, such a system failure could lead tolife threatening hypocalcemia within 10-20 minutes. Routine laboratorymonitoring every 6 hours as done in current clinical practice will notbe able to detect such a problem in a timely manner. Therefore, realtime (online) monitoring of calcium and magnesium levels in the systemicplasma of the patient is needed.

The present invention provides a novel, mathematically exacting,continuous monitoring method to address the above problem. The methodutilizes the knowledge that the composition of the patient's systemicplasma can be back-calculated from the composition of the ultrafiltrate,knowing exactly what composition fluids and in what amounts were infusedinto the systemic blood in the arterial limb of the circuit beforeultrafiltration and the sieving of individual solutes on the filter.This data is readily available in a given treatment. These calculationshave been described previously herein, including corrections for accessrecirculation, when present. The method also utilizes the simultaneousmeasurement of ionized citrate and ionized calcium and/or ionizedmagnesium and/or any of their complexes with citrate. The final methodand detections used may differ slightly from what is described hereinbased on future clinical experience, but the method according to thepresent invention includes the simultaneous measurement of the relevantinteracting cations and anions. The method also utilizes the applicationof chemical and mathematical principles governing the interactions ofthese ions in the ultrafiltrate (these interactions have been elucidatedin detail in the literature) with the specific purpose to derive thetotal calcium and total citrate levels in the ultrafiltrate in real timefor safety monitoring of the RCA for CRRT procedure without any need tointerrupt or modify the citrate anticoagulation.

The back-calculation of plasma concentration from ultrafiltrateconcentration may be accomplished in CVVH and the calculations used aredisplayed in FIGS. 29 a-29 c for a solute that distributes only into theplasma volume and not into the red blood cells. Calcium and citrate bothdistribute in this way. The calculations can also be performed whendiffusion-based clearance is used (dialysis) or when a mixture ofdialysis and convection is used (hemodiafiltration), and are notdiscussed here as they are known to those skilled in the art using thegeneral concept of dialysance. The use of the online clearance functionof the citrate sensor according to the present invention will verifythrough the measured D_(Bolus) (and by using the separately measured R)the accuracy of predictions of solute movement on the filter based ontheoretical calculations under these more complex circumstances.

Ionized calcium in the ultrafiltrate can be measured with a calciumselective electrode. Such electrodes are in routine clinical use todayand could be easily adapted to be inserted into the CRRT circuiteffluent line. Unfortunately, these electrodes can be fairly errorprone, require regular calibration and testing for accuracy and, withprolonged use, the electrode solutions will get depleted requiringmaintenance or replacement of the electrode. While a calcium electrodemay be used, the present invention also contemplates the use ofno-maintenance, possibly disposable optical calcium sensors (optrodes orchemical-optical chips) for the calcium sensor. Such optrodes have beendescribed in the literature and have many advantages over traditionalcalcium electrodes. Magnesium movement in the CRRT circuit parallelscalcium movement. Magnesium replacement is also completely coordinatedwith calcium by virtue of being in the same replacement infusionsolution. Therefore, only one of the two ions needs to be monitoredduring CRRT as there is not even any theoretical possibility of only oneion level becoming abnormal separate from the other as a consequence ofthe RRT procedure (it could, however, occur as a consequence of rareclinical situations and stemming from derangements in the patient'sphysiology). Nevertheless, if clinically desirable, duplicate monitoringcould be done with a magnesium selective electrode or preferably with amagnesium selective optrode or chemical-optical chip.

One problem inherent to the measurement of calcium or magnesium by anymethod online (electrode or optrode or other) is that these methodsdetect the ionized Ca²⁺ or Mg²⁺ species. Unfortunately, in thecitrate-rich CRRT effluent, 80-90% of calcium is bound by citrate and isnot available for measurement as the ionized form. To circumvent this,periodic cessation of citrate infusion into the circuit could beconsidered but is not especially feasible as it involves the risk ofclotting. It would also have to be done every 5-10 minutes at thehighest blood flows targeted by the RCA system. The neutralization ofthe chelating effect of citrate by either eliminating it on an anionexchange resin or by acidifying the effluent to about pH 2 are bothcumbersome and predictably prone to errors. Fortuitously, the detailedunderstanding of the chemical interactions of various ions in theultrafiltrate affords a convenient and precise solution to this problemwithout the above undesirable maneuvers.

The solution requires the additional measurement of the free, 3-valentnegatively charged citrate anion in the ultrafiltrate. This may beaccomplished most conveniently by the method discussed earlier hereinregarding the citrate sensor (see Parker et al. above). In thatpublication, the effect of competing divalent metal ions on citratebinding to the detecting complex were not investigated, but it is highlylikely that the europium-ligand complex will only bind the free,trivalent negative citrate anion with high affinity and therefore willbe eminently suitable for its selective detection in the CRRT effluent.In addition, the present invention also envisions the possible use ofother citrate detection methods. The most promising alternative may bethe method described by Anslyn et al. to detect calcium and citratesimultaneously and or building citrate optrodes where the citrate anionis bound by a specific receptor protein or antibody that was engineeredto act as a molecular switch to transmit a fluoroprobe generated opticalsignal upon binding with citrate. The receptor peptide may have to bemodified with molecular mutagenesis to optimize its specificity for thetarget trivalent citrate anion and increase pH independence of thebinding in the range 6.5-7.5. Such molecular engineering is certainlyfeasible with currently available biotechnology. In general, allpossible technologies that could be adapted for simple and inexpensivemeasurement of citrate in the effluent are fully contemplated for usewith the method according to the present invention. It may also bepossible to engineer receptor peptides that selectively bind theMg-citrate and or Ca-citrate complex enabling their independentmeasurement. Finally, one or more different citrate sensors could bedeployed simultaneously.

The CRRT effluent fluid contains a multitude of positively andnegatively charged anions, many of which will interact and formcomplexes with each other. For the purpose of safety monitoring of theRCA for CRRT procedure, the quantitatively most important positive ionsare sodium, calcium and magnesium and the quantitatively most importantanions are chloride, bicarbonate, citrate, phosphate and lactate. Thechemical principles governing the interactions of these anions in humanplasma and ultrafiltrate were described in a series of classicphysiological experiments (see Walser, J. Phys. Chem. 1961, 65, 159;Walser, Journal of Cellular & Comparative Physiology. 55:245-50, 1960June; Walser, J Clin Invest. 1961 April; 40(4): 723-730). The scientistsused ultrafiltration of plasma as a research tool; extracorporeal bloodpurification for renal replacement therapy was in its infancy at thetime. The implications of the published science for RCA seem to have notbeen recognized to date. Following from the published work, themeasurement of total calcium in the ultrafiltrate is accomplished asfollows in Equation 7:

K _(CaCit−)=((Ca ²⁺)_(free)*(Cit ³⁻)_(free))/(CaCit ⁻)  7)

Where:

K_(CaCit−)=the dissociation constant of the ionic calcium-citratecomplex (constant);(Ca²⁺)_(free)=the free ionized calcium concentration (measured by thecalcium sensor)(Cit³⁻)_(free)=the free ionized trivalent citrate concentration(measured by the citrate sensor)(CaCit⁻)=the calcium-citrate ionic complex with a single negative chargeThe dissociation constant has a fixed value at a given temperature andionic strength of the solution. Since the human plasma has a very narrowrange of acceptable (compatible with life) ion concentrations for allmajor ionic species and since the pre-filter fluids also have a nearphysiological composition (except for the presence of citrate), theionic strength of the CRRT effluent can be considered constant andeliminated as a variable. Also, the warming of the replacement fluidensures that the temperature of the ultrafiltrate is kept constant near37 C. Therefore, the K_(CaCat−) dissociation constant will be a fixedvalue under the operating conditions of CRRT. This allows us torearrange Equation 7 to express the amount of calcium complexed withcitrate in Equation 7*:

(CaCit ⁻)=((Ca ²⁺)_(free)*(Cit ³⁻)_(free) /K _(CaCit−)  7*)

It is of note that all variables on the right side above are measured orconstant, therefore (CaCit⁻) can be expressed continuously in real time.The effluent Ca also exists in complex with phosphate, lactate andbicarbonate. Complex formation with chloride does not occur. However,complex formation with phosphate will be minimized by keeping theeffluent pH around 6.6-7.0 (by using acid citrate anticoagulant) atwhich pH most phosphate will be in the H₂PO₄ ⁻ form that does not bindcalcium in a significant manner. The amount of calcium bound tobicarbonate and lactate is minimal and constant, and at worst can beaccounted for by a constant correction factor in the equation(designated F_(Ca)). Finally, the impact of high clearance CRRT willserve to normalize and standardize bicarbonate, phosphate and all otherorganic anion and possibly even lactate concentrations in the plasma andultrafiltrate after a few hours of operation. Therefore, the targetvariable, the total calcium concentration in the effluent can beexpressed as follows in Equation 8:

(Ca)_(total)=(Ca ²⁺)_(free)+(CaCit ⁻)+F _(Ca)  8)

This can be rearranged using Equation 7* to yield Equation 8*:

(Ca)_(total)=(Ca ²⁺)_(free)*(1+((Cit ³⁻)_(free) /K _(CaCit−)))+F_(Ca)  8*)

(The F_(Ca) is a minor constant factor to account for calcium bound toother anions (bicarbonate, lactate, phosphate, others) that is includedfor sake of completeness but is likely to be clinically not relevant.)Similar determinations can be done for magnesium that behaves similarlyto calcium except that it may bind with citrate with about 2.5 times ashigh affinity as shown in Equation 9:

(Mg)_(total)=(Mg²⁺)_(free)*(1+((Cit ³⁻)_(free) /K _(MgCit−)))+F_(Mg)  9)

The variables denote the same as for calcium except that magnesium isused as the metal ion.

The K_(CaCit−) and K_(MgCit−) dissociation constants were previouslydetermined at a sodium concentration of 140 mmol/L and at 25 Celsiustemperature (see Am J Kidney Dis. 2005 March; 45(3):557-64; Curr OpinNephrol Hypertens. 1999 November; 8(6):701-7). Minor adjustments will beneeded as the effluent temperature will be around 37 C in clinicalpractice. This depends on the heat loss from the effluent fluid beforecontacting the sensor. A heater element on the effluent fluid line maybe deployed to ensure standard measurement conditions.

Finally, with the total effluent calcium and/or magnesium concentrationdetermined with clinically satisfactory accuracy, the back-calculationto the systemic plasma value can be performed immediately as describedin FIGS. 29 a-29 c and as will be apparent to those skilled in the art.(If both calcium and magnesium sensing is performed, the measurementscan be further checked for accuracy as follows: After several hours ofCRRT, the ratio of the determined total calcium and total magnesiumconcentrations in the ultrafiltrate must be equal to the ratio ofcalcium and magnesium in the replacement fluid based on the concept ofsteady state and neutral mass balance, unless a significantpathophysiologic process results in the release or sequestration ofcalcium in the patient's body disproportionate to magnesium movement.)

As far as the measurement of total citrate in the CRRT effluent isconsidered, similar principles can be used to derive this value. For thecomplete and detailed explanation of the calculations, see Walser et alas described above. The equation for citrate is as follows in Equation10:

(Cit)_(total)=(Cit³⁻)_(free)*(1+((Na⁺)_(free)/K_(NaCit2−))+((Ca²⁺)_(free) /K_(MgCit−))+((Mg²⁺)_(free) /K _(MgCit−)))  10)

Where the variables are:(Cit)_(total) is the total citrate concentration of the effluent;(Cit³⁻)_(free)=the free ionized trivalent citrate concentration(measured by the citrate sensor);(Na⁺)_(free)=the free ionized sodium concentration of the effluent(after a few hours of operation of the CRRT procedure this will benormalized to a constant at 140 mmol/L and can also be derived ifnecessary by measuring the conductivity of the effluent with clinicallysufficient accuracy);K_(NaCit2−)=the dissociation constant of the ionic sodium-citratecomplex (constant);K_(CaCit−)=the dissociation constant of the ionic calcium-citratecomplex (constant);K_(MgCit−)=the dissociation constant of the ionic magnesium-citratecomplex (constant);

In the clinical setting, the contribution of sodium will be constant andwill likely not need to be measured, just expressed with a constantcorrection factor (may be denoted as an optional F_(Cit)). The mostscientifically accurate determination of the total citrate level in theeffluent requires the simultaneous measurement of the free ionizedcalcium, free ionized magnesium and the free trivalent ionized citrate.However, as discussed previously herein, the movement of magnesium iscompletely coordinated with calcium in the CRRT circuit according to thepresent invention. Therefore, as long as the magnesium supplement isexclusively provided as a combined, fixed ratio infusion with calcium,the contribution of magnesium bound citrate can be derived frommeasuring the calcium only, assuming that the ratio of total effluentcalcium to total effluent magnesium will be equal to the ratio ofcalcium to magnesium in the combined replacement infusion. This isexplained below.

Equation 11 (valid under steady state and without gross perturbations ofbody calcium or magnesium balance):

(Ca)_(total)/(Mg)_(total) =R _(Ca/Mg)  11)

By rearranging the above, we get Equation 11*:

(Mg)_(total)=(Ca)_(total) /R _(Ca/Mg)  11*)

Where the new variable is:R_(Ca/Mg)=the fixed molar ratio of calcium and magnesium in thereplacement fluid (around 2-2.5; the exact value will be chosen afterextensive clinical testing)

(Ca)_(total)=(Ca²⁺)_(free)+(1+((Cit ³⁻)_(free) /K _(CaCit−)))+F_(Ca))  8*)

(Mg)_(total)=(Mg²⁺)_(free)*(1+((Cit ³⁻)_(free) /K _(MgCit−)))+F_(Mg)  9)

Therefore, the solution in Equation 12 yields:

(Mg²⁺)_(free)=((((Ca²⁺)_(free)*(1+((Cit ³⁻)_(free) /K _(CaCit−)))+F_(Ca))/R _(Ca/Mg))−F _(Mg))/(1+((Cit ³⁻)_(free) /K _(MgCit−)))  12)

The so derived (Mg²⁺)_(free) than can be inserted into Equation 10 (inlieu of a measured value) to determine the total citrate concentration.An alternative is the measurement of free ionized magnesium and thederivation of calcium along the same principles, as in Equation 13:

(Ca²⁺)_(free)=((((Mg²⁺)_(free)*(1+((Cit ³)_(free) /K _(MgCit−)))+F_(Mg))/R _(Mg/Ca))−F _(Ca))/(1+((Cit ³⁻)_(free) /K _(CaCit−)))  13)

Where R_(Mg/Ca)=the fixed molar ratio of magnesium and calcium in thereplacement fluid and naturally:

R _(Ca/Mg)=1/R _(Mg/Ca)  14)

However, since in rare clinical conditions, for example in hypercalcemiaof malignancy or hungry bone syndrome, the mass balance of calcium andmagnesium can become dissociated inside the patient's body, and alsobecause of the vital importance of systemic ionized calcium, ionizedcalcium monitoring may be always performed with or without ionizedmagnesium monitoring).In Equations 12 and 13, the principle was used that when two variablesout of the three variables of interest (ionized Ca2+, ionized Mg2+ andionized trivalent Cit3−) are measured, the third one can be calculatedusing the added information from equation 11. Using this principle, thefree trivalent citrate can also be calculated, when the ionized Ca andionized Mg is measured as long as Equation 11 applies as true (this willbe the case in most clinical situations). The solution of Equations 11,8* and 9 for the free trivalent citrate concentration yields Equation15:

(Cit ³⁻)_(free)=((R _(Ca/Mg)*((Mg²⁺)_(free) +F _(Mg)))−((Ca²⁺)_(free) +F_(Ca)))/((((Ca²⁺)_(free) *K _(MgCit−))−(R _(Ca/Mg)*(Mg²⁺)_(free) *K_(CaCit−)))/(K _(CaCit−) *K _(MgCit−)))  15)

Equation 15 can be used when a specific citrate sensor is not yetclinically available and as long as accurate (Ca²⁺)_(free) and(Mg²⁺)_(free) measurements are available with ion specific electrodes.Equation 15 further assumes that Equation 11 is true. This will be thecase when there is no pathophysiologic process present in the patient'sbody that would result in the body absorption or release of calcium ormagnesium in a ratio different from the ratio of these ions in thecalcium plus magnesium replacement infusion fluid. As long as thesystemic plasma ionized calcium is maintained around the physiologic1.25 mmol/L, this will be true for the large majority of patients.

Overall, as stated earlier, the simultaneous measurement of the freeionized calcium, free ionized magnesium and the free trivalent ionizedcitrate may provide the best method of monitoring. However, Equation 15can be used with commercially available calcium and magnesium electrodesand is a better solution to the problem of citrate monitoring thananything existing in current practice until an ionized citrate sensorbecomes commercially available. The method according to the presentinvention includes the application of Equations 12, 13 and 15 orvariations of these equations based on the same principles tocontinuously compare and verify the data provided by the proposed threedifferent sensors. As long all of the sensors perform precisely, themeasured values of (Ca²⁺)_(free), (Mg²⁺)_(free) and (Cit³⁻)_(free)should fulfill the above equations.

Finally, with the total effluent citrate concentration determined withclinically satisfactory accuracy, the back-calculation to the systemicplasma value can be performed immediately as described in FIGS. 29 a-29c and as is apparent to those skilled in the art.

The above calculations are obviously not meant to be performed by theclinician at the bedside. However, when the OSS according to the presentinvention delivers the above measured values in real time, a smallcomputer integrated into the OSS can easily be programmed to process thedata as above and display the effluent values in real time. Thecalculation of the systemic plasma values then requires the OSS to haveinformation about the treatment settings (fluid flows and composition).This data can be provided by integrating the OSS into the CRRT device orcould be entered manually (as these variables typically do not needfrequent changes during the RCA for CRRT procedure) if the OSS isimplemented as a stand-alone citrate and calcium sensing safety device.

The OSS according to the present invention may improve the safety of RCAfor RRT as follows. The generalized concept of the OSS is outlined forthe safe monitoring of any water soluble, filterable substance in theeffluent line of the OSS circuit that is either normally present in thebody or is introduced by IV infusion through the fluid infusion pathwayof the CRRT circuit or by other means. One immediately feasible specificexample is the online monitoring of tight glycemic protocols. The OSS asa citrate sensor may be designed as a safety monitor for real-time,online detection of citrate accumulation in the patient who is receivingRCA during the delivery of CRRT whether in the form of continuousveno-venous hemofiltration (CVVH), continuous veno-venous hemodialysis(CVVHD) or continuous veno-venous hemodiafiltration (CVVHDF). The sensoreliminates the need for frequent laboratory testing to detect thiscomplication and is equally adaptable to intermittent hemodialysis (IHD)and continuous sustained low efficiency dialysis (c-SLED) performed withRCA as well.

The OSS as a citrate sensor may be designed to provide real-time, onlineclearance measurements (FIG. 34 c) for any type of blood purificationbased renal replacement therapy that utilizes RCA including CVVH,CVVHDF, CVVHD, and SLED as well as IHD. FIG. 34 c illustrates an onlinefilter clearance and patency monitor according to the present invention,where the citrate concentration is measured by a citrate sensor in thedrain circuit of an RRT machine utilizing RCA. Increasing the infusionof citrate into the blood entering the CRRT circuit for a short periodof time produces a corresponding response in the citrate measured in thedrain circuit. Data from the transient increase in citrate concentrationcan then be used to determine the dialyzer citrate clearance online.Accuracy may be superior to the existing online clearance monitoringtechnology based on conductivity measurements, depending on theresolving accuracy of the citrate sensor implementation.

The OSS as a citrate plus calcium (and magnesium) sensor may be designedto provide data that allows accurate, real-time display of the patient'ssystemic calcium, magnesium and citrate levels for safety and the dosingof calcium and magnesium replacement infusions appropriate for thelosses of these ions through the CRRT circuit, thereby reducing andlikely obviating the need for frequent calcium and magnesium monitoringduring the CRRT procedure. It also allows for the mathematically exactderivation of the individual patient's rate of citrate metabolism, whichin turn allows the selection of the most appropriate RCA fluidcompositions for the patient to maintain acid-base balance.

The OSS according to the present invention may be designed to monitororgan function in real time with specific examples of monitoring liverfunction through citrate metabolism and monitoring glomerular filtrationrate and renal tubular function through the detection of inulin and PAHlevels in the effluent of CRRT circuits. The ability to monitor livermetabolic function in real time can be of great benefit in acute- orchronic liver failure and pre- and post-liver transplantation. Theability to monitor glomerular filtration rate and or renal tubularsecretory function will be of great importance in the future, whenassessing when to stop CRRT because of recovery of renal function willbe a clinical challenge in non-oliguric ARF patients. These patientswill all have normal serum chemistries on CRRT as a result of the highCRRT clearance goals gradually becoming the standard of practice. TheOSS can monitor any organ, including the hear as long as awater-soluble, filterable compound is identified that is clearedexclusively by the target organ at a rate in excess of its clearancethrough the extracorporeal blood circuit.

The OSS of the present invention as a citrate, calcium and magnesiumsensor will allow RCA for RRT to be delivered safely with possibly nointervention and monitoring from health care personnel. The OSS as partof the RCA home system with OCM and OSS with single needle access willrepresent a major safety improvement over any home RRT machine and willallow RCA (that is more powerful than heparin and has no systemicbleeding effects) to enter the home setting for nocturnal renalreplacement therapies.

While embodiments of the invention have been illustrated and described,it is not intended that these embodiments illustrate and describe allpossible forms of the invention. Rather, the words used in thespecification are words of description rather than limitation, and it isunderstood that various changes may be made without departing from thespirit and scope of the invention.

What is claimed is:
 1. A system for regional citrate anticoagulation inan extracorporeal blood circuit including an arterial blood linearranged to be connected to a vascular access for withdrawing blood froma patient and a venous blood line arranged to be connected to thevascular access for returning blood to the patient, the systemcomprising: a hemofilter in fluid communication with the arterial andvenous blood lines and having a dialysis-fluid in connector and adialysis-fluid out connector; a first pre-filter infusion line and pumphaving a connection to the arterial blood line upstream from thehemofilter for infusing a first pre-filter infusion solution comprisinga citrate anticoagulant-containing solution; a second pre-filterinfusion line and pump capable of a connection to the arterial bloodline upstream from the hemofilter for infusing a second pre-filterinfusion solution comprising a first bicarbonate-containing solution; afresh dialysis fluid line and pump capable of a connection to thehemofilter dialysis-fluid in connection for providing dialysis with asecond bicarbonate-containing solution countercurrent to a direction ofblood flow in the hemofilter; a post-filter infusion line and pumpcapable of a connection to the venous blood line downstream from thehemofilter for infusing a post-filter infusion solution comprising athird bicarbonate-containing solution; an effluent fluid line and pumpconnected to the hemofilter dialysis-fluid out connection for receivingfilter effluent fluid; an additional infusion line and pump having aconnection to the venous blood line downstream from the connection ofthe post-filter infusion line for infusing an additional infusionsolution comprising a calcium- and magnesium-containing solution; and amonitor for determining a performance of the hemofilter in removingcitrate from the blood.